Amino heteroaryl kinase inhibitors

Abstract

Provided herein are novel compounds (e.g., Formula I) related to cyclin dependent kinases (CDKs), pharmaceutical compositions, and methods of use. The compounds herein are typically CDK4 inhibitors that are useful in the treatment of various diseases or disorders, such as cancer. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to International Patent Application No. PCT / CN2022 / 109075 filed on July 29, 2022, International Patent Application No. PCT / CN2022 / 128578 filed on October 31, 2022, and International Patent Application No. PCT / CN2023 / 078781 filed on February 28, 2023, the entire contents of each of these international patent applications are incorporated herein by reference. Technical Field

[0003] In various embodiments, the present disclosure generally relates to novel Heteroaryl Compounds, compositions comprising the same, methods of making the same, and methods of using the same, for example, for inhibiting cyclin-dependent kinases and / or for treating or preventing the various diseases or disorders described herein. Background Art

[0004] Unrestricted cell growth is a typical hallmark of cancer, and disrupted cell cycle regulation is a common feature in malignant cells.Cyclin-dependent kinases (CDKs) are a family of serine / threonine protein kinases that regulate mammalian cell division and proliferation.At least 20 CDKs and 29 cyclins have been identified in human cells (Cao et al., BMC Evol. Biol [BMC Evolutionary Biology], 2014; 14: 10). In addition to regulating cell cycle progression, these CDKs and cyclins also play an important role in regulating transcription, DNA repair, differentiation and apoptosis (Palmer and Kaldis, Semin Cell Dev Biol [Cell and Developmental Biology Seminar], 2020; 107: 54-62).

[0005] CDK4 and CDK6 are key regulators of G1-S transition. D-type cyclins form a complex with CDK4 / 6 and phosphorylate retinoblastoma (Rb) protein. This relieves the inhibition of Rb-mediated transcription factor E2F and leads to S phase entry. The CDK4 / 6-cyclin D-Rb pathway is often disturbed in human cancers. Amplification of CDK4 / 6 and cyclin D1, overexpression of D-type cyclins, mutations, genetic deletions or transcriptional silencing of endogenous CDK4 / 6 inhibitor p16 (CDKN2A) have all been reported as mechanisms leading to pathway activation (Dickson, Mol Cancer Res. [Molecular Cancer Research] 2014; 20: 3379-3383). In breast cancer, dysregulation of the CDK4 / 6 pathway is associated with resistance to endocrine therapy (Ding et al., Int J Mol Sci. [International Journal of Molecular Sciences] 2020; 21: 1960).

[0006] In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor types. CDK4 / 6 inhibitors have been shown to be effective in the treatment of human epidermal growth factor 2 (HER2)-negative, estrogen receptor (ER)-positive breast cancer when used together with endocrine therapy. Therefore, different CDK4 / 6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved for combination with endocrine therapy in first-line or second-line scenarios (Cogliati et al., Life, 2022; 12: 378). Recently, abemaciclib has also been approved for adjuvant treatment of early breast cancer.

[0007] Although CDK4 / 6 inhibitors have been successful in the clinic, treatment-related adverse reactions (especially hematological toxicity such as neutropenia) prevent the continued administration of CDK4 / 6 inhibitors. Currently, both palbociclib and ribociclib are administered on a three-week / one-week schedule. Mouse genetics and other emerging data suggest that the observed hematological toxicity may be related to CDK6-cyclin D3 inhibition (Sicinska et al., Mol Cell Biol [Molecular Cell Biology], 2006; 26: 8052-8060; Cooper et al., Nat Immunol [Natural Immunology], 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 [Cancer Research], 2022; Electronic publication). Summary of the invention

[0008] Inhibitors that are specific for a particular CDK (e.g., CDK4) may have the advantage of an improved safety profile and may allow for improved dosing regimens and higher dosing, and may result in deeper target inhibition, better efficacy, and potentially overcome drug resistance. There remains a need for CDK inhibitors, such as selective CDK4 inhibitors, such as those with improved efficacy and reduced clinical side effects.

[0009] In various embodiments, the present disclosure provides novel compounds that can inhibit CDK, such as selectively inhibiting CDK4. The compounds and compositions herein can be used to treat various diseases or disorders associated with abnormal CDK4 activity, such as hormone receptor-positive, HER2-negative breast cancer.

[0010] Some embodiments of the present disclosure relate to compounds having Formula I or pharmaceutically acceptable salts thereof,

[0011]

[0012] Wherein these 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 one of Examples 1-111, or any specific compound disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof.

[0013] 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 generally be formulated for oral administration.

[0014] In some embodiments, the disclosure also provides a method of inhibiting CDK activity, such as CDK4 activity, in a subject or biological sample. In some embodiments, the method includes contacting a subject or biological sample with an effective amount of one or more compounds of the disclosure (e.g., a compound having Formula I (or any subformula provided in the text, 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), any one of Examples 1-111, or any specific compound disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising the same.

[0015] In some embodiments, the disclosure provides a method for treating or preventing a CDK-mediated disease or disorder in a subject in need. In some embodiments, the method includes administering to the subject an effective amount of one or more compounds disclosed herein or a pharmaceutical composition herein. In some embodiments, the method includes administering to the subject an effective amount of a compound having Formula I (or any subformula provided by the text, for example, 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), any one of Examples 1-111, or any specific compound disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0016] In some embodiments, the disclosure also provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound having 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), any one of Examples 1-111, or any specific compound 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 cancer, thyroid cancer, and combinations thereof. In some embodiments, the cancer is selected from the following breast cancer: ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC); and inflammatory breast cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from the following breast cancer: endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the cancer is advanced or metastatic breast cancer. In some embodiments, the cancer is ovarian cancer.

[0017] Administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the 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.

[0018] The compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments according to the methods described herein, one or more compounds of the present disclosure can be administered as the only one or more active ingredients. In some embodiments, the methods herein also include administering to the subject an additional therapeutic agent, such as an additional anticancer agent described herein.

[0019] It should be understood that the foregoing summary of the invention and the following detailed description are exemplary and explanatory only and are not restrictive of the invention herein. DETAILED DESCRIPTION

[0020] In various embodiments, the disclosure provides compounds and compositions that are useful for inhibiting a CDK, such as CDK4, and / or treating or preventing various diseases or disorders described herein, such as cancer.

[0021] Compound

[0022] The compounds disclosed herein are generally aminopyridine or aminopyrimidine derivatives having Formula I as described herein. The compounds herein generally can inhibit CDKs, such as CDK4. In some embodiments, the compounds herein can selectively inhibit CDK4 relative to other CDKs.

[0023] Formula I

[0024] In some embodiments, the present disclosure provides a compound having Formula I or a pharmaceutically acceptable salt thereof:

[0025]

[0026] in:

[0027] L 1 is an optionally substituted phenylene, an optionally substituted 5- or 6-membered heteroarylene, an optionally substituted 4-8-membered heterocyclylene, or an optionally substituted C 3-8 Carbocyclylene;

[0028] R 1 is hydrogen, OH, NH2, NHCH3 or N(CH3)2;

[0029] X is N or CR 10 ;

[0030] R 2 is an optionally substituted ring system selected from a 10-membered heteroaryl, a 9-12-membered bicyclic heterocycle, or a 12-16-membered heteroaryl or a heterocyclic structure having three or more rings, wherein the ring system includes at least one phenyl or heteroaryl ring, and wherein R 2 is bonded to the remainder of Formula I via a ring atom of the phenyl or heteroaryl portion of the ring system;

[0031] R 3 is hydrogen, deuterium, halogen (e.g., F, Cl), CN, OR 11 NR 12 R 13 、C(O)NR 12 R 13 、COOR A , COR 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 3-8carbocyclyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

[0032] R 4 is hydrogen, deuterium, halogen (eg, F), optionally substituted C 1-6 Alkyl, or NR 12 R 13 ;

[0033] in:

[0034] R 10 is hydrogen, halogen (eg, 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;

[0035] 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 4-10 membered heterocyclyl; or an oxygen protecting group;

[0036] R 12 and R 13 Each of the following, at each occurrence, is independently 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 4-10 membered heterocyclyl; or a nitrogen protecting group; or R 12 and R 13 may be linked to form an optionally substituted 4-10 membered heterocyclyl or 5- or 6 membered heteroaryl;

[0037] R A is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (eg, 5- or 6-membered heteroaryl), optionally substituted 4-10 membered heterocyclyl; or an oxygen protecting group; and

[0038] R B is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8carbocyclyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted heteroaryl (eg, 5- or 6-membered heteroaryl).

[0039] In one embodiment, R 2 The phenyl or heteroaryl portion of (attached to the remainder of Formula I) is not fused to a 5-membered heteroaryl group.

[0040] In some embodiments, compounds of Formula I (including any applicable subformulae described herein) may contain one or more asymmetric centers and / or axial chirality and may therefore exist in multiple stereoisomeric forms (e.g., enantiomers and / or diastereomers). In some embodiments, compounds of Formula I may exist as individual enantiomers and / or diastereomers (if applicable), or as mixtures of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). In some embodiments, compounds of Formula I (including any applicable subformulae as described herein) may have an enantiomeric excess ("ee") greater than 60%, such as greater than 80% ee, greater than 90% ee, greater than 95% ee, greater than 98% ee, greater than 99% ee, or with undetectable amounts of other enantiomers, when applicable. In some embodiments, compounds of Formula I (including any applicable subformulae as described herein) may also exist as mixtures of stereoisomers (in any ratio), such as racemic mixtures, when applicable.

[0041] In some embodiments, compounds of formula I (including any applicable subformula as described herein) can exist as isotopically labeled compounds, particularly deuterated analogs, wherein one or more hydrogen atoms of the compound of formula I are replaced by deuterium atoms having an abundance higher than its natural abundance, such as when the compound has a CH3 group, it is a CD3 analog. Without wishing to be bound by theory, it is believed that deuterium substitution at certain positions (e.g., those explicitly specified herein) can result in compounds having better pharmacokinetic characteristics when compared with their hydrogen counterparts (i.e., with natural abundance), and therefore can have better in vivo pharmacodynamic results. Compounds with specific deuterium substitutions can be prepared by using commercially available deuterium enrichment reagents (such as deuterium gas, deuterium oxide (D2O), deuterated formic acid (DCOOD), deuterated methyl iodide (CD3I), deuterated methanol (CD3OD), deuterated sodium oxide (NaOD), sodium borodeuteride (NaBD4), lithium aluminum deuteride (LiAlD4), etc.) methods.

[0042] It should be apparent to those skilled in the art that, in certain cases, compounds having Formula I may exist as a mixture of tautomers. The present disclosure is not limited to any particular tautomer. Rather, the present disclosure encompasses any and all such tautomers, whether or not explicitly drawn or mentioned.

[0043] Typically, X in Formula I is N, and compounds having Formula I can be characterized as having Formula IA:

[0044]

[0045] Where L 1 , R 1 , R 2 , R 3 , and R 4 Includes any of those described herein in any combination.

[0046] In some embodiments, X in Formula I may be CR 10 , where R 10 As defined herein. For example, in some embodiments, R 10 may be hydrogen, and the compound having formula I may be characterized as having formula IB:

[0047]

[0048] Where L 1 , R 1 , R 2 , R 3 , and R 4 Includes any of those described herein in any combination.

[0049] A variety of groups are suitable as L in formula I 1 For example, in some embodiments, L in Formula I 1 It can be an optionally substituted phenylene. In some embodiments, L in Formula I 1 It may be an optionally substituted 5- or 6-membered heteroarylene group, for example those having 1 to 3 ring heteroatoms independently selected from N, O and S, for example pyridylene, for example It is optionally substituted. For example, in some embodiments, L in Formula I 1 Can be wherein the pyridinyl group is optionally substituted by a 5-membered heteroaryl group, such as pyrazole or imidazole. 1 Can be selected from: Typically, in such embodiments, R 1 Can be hydrogen. In some embodiments, L in Formula I 1It may be an optionally substituted 4-8 membered heterocyclylene, for example, a monocyclic or bicyclic (eg, 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 It may be optionally substituted C 3-8 Carbocyclylene, for example, a monocyclic or bicyclic (eg, fused, bridged or spiro bicyclic) carbocyclylene.

[0050] In some specific embodiments, the compounds of Formula I herein can be characterized as having a structure according to Formula A:

[0051]

[0052] in:

[0053] Q is

[0054] (1) O;

[0055] (2)NR 14 , where R 14 It is hydrogen, G A 、SO2G A 、SO2NG B G C 、S(O)(NH)G A , COG A ,COOG A , or C(O)NG B G C ;

[0056] (3)CR 15 R 16 , where R 15 and R 16 are joined together with the carbon atom to which they are attached to form an optionally substituted 4-6 membered heterocyclic ring having 1 or 2 ring heteroatoms independently selected from O and N; or

[0057] (4) does not exist;

[0058] r1 is 1, 2, or 3; and

[0059] r2 is 0, 1, or 2;

[0060] When valency permits, n is 0, 1, 2, 3 or 4; and

[0061] (i)R 100 At each occurrence, is independently selected from halogen (e.g., F or Cl), CN, OH, COOH, G A , OG A NG B G CNG B G C SO2G A NG B G C SO2NG B G C NG B G C S(O)(NH)G A NG B G C COG A NG B G C COOG A NG B G C C(O)NG B G C 、SO2G A 、SO2NG B G C 、S(O)(NH)G A , COG A ,COOG A , or C(O)NG B G C ;or

[0062] (ii) R 100 Two instances of are joined together with one or more intervening atoms to form an optionally substituted ring, such as an optionally substituted 3-6 membered ring, and any remaining R 100 as defined in (i) at each occurrence;

[0063] in:

[0064] G A is independently at each occurrence an optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (eg, 5- or 6-membered heteroaryl), or optionally substituted 4-10 membered heterocyclyl; and

[0065] G B and G C Each of the following, at each occurrence, is independently 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 4-10 membered heterocyclyl; or a nitrogen protecting group; or G B and G Cmay be linked to form an optionally substituted 4-10 membered heterocyclyl or 5- or 6 membered heteroaryl,

[0066] Where R 1 , R 2 , R 3 , and R 4 Includes any of those described herein in any combination.

[0067] In some embodiments, the compound having formula A may be a compound having the stereochemistry as shown in formula A-S1 or A-S2:

[0068]

[0069] In some preferred embodiments, the compound of formula A may exist as a stereoisomer of formula A-S1, for example with an ee greater than 60%, preferably greater than 80%, greater than 90%, greater than 95%, greater than 98%, greater than 99% ee, or with an undetectable amount of an enantiomer according to formula A-S2.

[0070] In some embodiments, the compound having formula A may be a compound having the stereochemistry as shown in formula A-S3 or A-S4:

[0071]

[0072] In some embodiments according to Formula A, n is 0. In some embodiments according to Formula A, n is 1 or 2, and R 100 is independently selected at each occurrence from F, Cl, CN, OH, C optionally substituted with F 1-4 alkyl, optionally substituted with F 1-4 alkoxy, and C optionally substituted by F 1-4 Heteroalkyl.

[0073] In some embodiments according to Formula A, n is 1, and R 100 It is F, Cl, CN, OH, methyl, fluorine-substituted methyl such as CF3, methoxy, or fluorine-substituted methoxy.

[0074] 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.

[0075] In some embodiments, Q in Formula A is absent (ie, Q is a bond connecting two carbon atoms adjacent to Q in Formula A).

[0076] In some embodiments, Q in Formula A is O.

[0077] In some embodiments, in Formula A, r1 is 1, r2 is 1, and Q is O. For example, in some embodiments, Part can be Preferably, the stereochemistry is In one embodiment, the portion is In one embodiment, the portion is

[0078] In some embodiments, the compound having formula A can be characterized as having a structure according to formula A-1 or A-2:

[0079]

[0080] in:

[0081] R 17 is optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocycle, or optionally substituted 5 or 6 membered heteroaryl.

[0082] For example, in some embodiments, R 17 yes

[0083] (1)C 1-4 Alkyl, which is optionally substituted with 1-3 substituents independently selected from deuterium, F, and OH, such as CHF2, CF3, etc.;

[0084] (2) phenyl, pyridyl, or pyrimidinyl, each of which is optionally substituted with 1-3 independently selected from deuterium, halogen, CN, OH, C optionally substituted with F 1-3 alkyl, or C optionally substituted by F 1-3 Substitution of the alkoxy group; or

[0085] (3) 5-membered heteroaryl, which is optionally substituted by 1-3 independently selected from deuterium, halogen, CN, OH, C optionally substituted by F 1-3 alkyl, or C optionally substituted by F 1-3 The substituents of the alkoxy group are substituted.

[0086] In some embodiments, R 17 Can be C 1-4 Alkyl, (C 1-4 Alkylene) j -C 3-6 Cycloalkyl, (C 1-4 Alkylene) j -(a 4-8 membered monocyclic heterocyclyl having one or two ring heteroatoms independently selected from N, O and S), or (C1-4 Alkylene) j -(5- or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S),

[0087] where j is 0 or 1, and the C 1-4 Alkylene is a straight or branched alkylene chain optionally substituted with F; and

[0088] Among them C 1-4 Alkyl, C 3-6 Each of the cycloalkyl, 5- or 6-membered heteroaryl and 4-8-membered monocyclic heterocyclyl is optionally substituted by one or more (e.g. 1, 2 or 3) independently selected from oxo (when valence permits), halo (e.g. F), G 1 ,OH,OG 1 、NH2、NH(G 1 ) and N(G 1 )(G 1 ) is substituted by a substituent,

[0089] Among them G 1 is independently (1) at each occurrence optionally replaced by 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 1-4 alkyl, or (2) optionally substituted by 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 Cycloalkyl;

[0090] When substituted, the C 1-4 Alkyl, C 3-6 The cycloalkyl, 5- or 6-membered heteroaryl, or 4-8-membered monocyclic heterocyclyl is preferably substituted with 1, 2 or 3 each independently being F, Cl, CN, OH, C 1-4 alkyl, or C optionally substituted by F 1-4 In some embodiments, j is 0. In some embodiments, j is 1, and the C 1-4 Alkylene is a straight or branched alkylene chain, for example CH2.

[0091] In some embodiments, R 17 Can be C 1-4 Alkyl, such as methyl, ethyl, isopropyl, etc. In some embodiments, R 17 It may be C optionally substituted by F 1-4 alkyl.

[0092] In some embodiments, R 17 Can be C 3-6 Cycloalkyl, which is optionally substituted, for example with substituents as described herein.

[0093] In some embodiments, R 17 It may be a 4-8 membered monocyclic heterocyclyl having one or two ring heteroatoms independently selected from N, O and S, which is optionally substituted, for example, with the substituents described herein.

[0094] In some embodiments, R 17 It may be a 5-membered heteroaryl group, which is optionally substituted, for example by C 1-4 Alkyl groups, such as R 17 Can be selected from:

[0095]

[0096] In some embodiments, R 17 It may be phenyl or a 6-membered heteroaryl having 1-3 ring nitrogen atoms, wherein the phenyl or 6-membered heteroaryl is optionally substituted by one or more (eg, 1, 2 or 3) independently selected from halo (eg, F), G 1 ,OH,OG 1 、NH2、NH(G 1 ) and N(G 1 )(G 1 ) is substituted by a substituent,

[0097] Among them G 1 is independently (1) at each occurrence optionally replaced by 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 1-4 alkyl, or (2) optionally substituted by 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 Cycloalkyl,

[0098] When substituted, the phenyl or 6-membered heteroaryl is preferably substituted by 1, 2 or 3 each independently being F, Cl, CN, OH, C optionally substituted by F. 1-4 alkyl, optionally substituted with F 1-4 The alkoxy substituents are substituted, more preferably, by 1 or 2 substituents each independently being F or methyl. For example, in some embodiments, R 17 Can be

[0099] In any embodiment herein, unless specified or otherwise contradicted by the context, R 1 It can be OH.

[0100] In any embodiments herein, X may be N unless specified or otherwise contradicted by context.

[0101] In any embodiment herein, unless specified or otherwise contradicted by context, L in Formula I (or any applicable subformula as described herein, such as Formula A, IA or IB) is 1 -R 1 Can be

[0102]

[0103] In any embodiment herein, unless specified or otherwise contradicted by context, L in Formula I (or any applicable subformula as described herein, such as Formula A, IA or IB) is 1 -R 1 Can be

[0104]

[0105] In some embodiments, L in Formula I (or any applicable subformula as described herein, such as Formula A, IA, or IB) 1 -R 1 yes

[0106] Where R 17 yes

[0107] (1)C 1-4 Alkyl, which is optionally substituted with 1-3 substituents independently selected from deuterium, F, and OH, such as CHF2, CF3, etc.;

[0108] (2) phenyl, pyridyl, or pyrimidinyl, each of which is optionally substituted with 1-3 independently selected from deuterium, halogen, CN, OH, C optionally substituted with F 1-3 alkyl, or C optionally substituted by F 1-3 Substitution of the alkoxy group; or

[0109] (3) 5-membered heteroaryl, which is optionally substituted by 1-3 independently selected from deuterium, halogen, CN, OH, C optionally substituted by F 1-3 alkyl, or C optionally substituted by F 1-3 The substituents of the alkoxy group are substituted.

[0110] For example, in some embodiments, R 17 It may be C optionally substituted with 1-3 F 1-4 In some embodiments, R 17can be phenyl, pyridyl, or pyrimidinyl, each of which is unsubstituted or substituted with 1 or 2 substituents each independently being F or methyl. 17 It may be pyrazole, imidazole or triazole, each of which is unsubstituted or optionally substituted with F. 1-3 In some specific embodiments, R 17 Can be

[0111]

[0112] In some embodiments, L in Formula I (eg, Formula A, IA, or IB) 1 -R 1 Can be selected from:

[0113]

[0114] A variety of groups are suitable for use as R in Formula I 2 For example, in some embodiments, R 2 It may be an optionally substituted 10-membered heteroaryl. 2 may be an optionally substituted 9-12 membered bicyclic heterocycle, wherein one of the two rings is a phenyl or heteroaryl ring, and R 2 The bicyclic system is connected to the rest of Formula I via a ring atom of the phenyl or heteroaryl portion. 2 may be an optionally substituted 12-16 membered heteroaryl or a heterocyclic structure having three or more rings, wherein at least one of the rings is a phenyl or heteroaryl ring, and R 2 The ring system is connected to the rest of Formula I via a ring atom of the phenyl or heteroaryl portion. 2 The phenyl or heteroaryl portion of (attached to the remainder of Formula I) is not fused to a 5-membered heteroaryl group.

[0115] In one embodiment, R 2 is an optionally substituted 10-membered heteroaryl group, wherein R 2 The bond to the rest of formula I is through the phenyl group, and the phenyl group is fused to the 6-membered heteroaryl group.

[0116] In one embodiment, R 2 is an optionally substituted 9-12 membered bicyclic heterocycle, wherein R 2 The bond to the rest of formula I is through the phenyl group, and the phenyl group is fused to a 5-8 membered heterocyclic ring.

[0117] In one embodiment, R 2 is an optionally substituted tricyclic heteroaryl group, wherein R 2The rest of Formula I is connected via a phenyl group (the first ring), which is fused to a 6-membered heteroaryl group (the second ring), and which is further fused to a 5- or 6-membered heteroaryl group (the third ring). In one embodiment, the third ring is a 5-membered heteroaryl group. In one embodiment, the third ring is a 6-membered heteroaryl group.

[0118] In one embodiment, R 2 is an optionally substituted tricyclic heterocycle, wherein R 2 The rest of Formula I is connected by a phenyl group (first ring), which is fused to a 6-membered heteroaryl group (second ring), and the 6-membered heteroaryl group is further fused to a 5- or 6-membered heteroaryl group 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.

[0119] In one embodiment, R 2 is an optionally substituted tricyclic heterocycle, wherein R 2 The rest of Formula I is connected by a phenyl group (the first ring), which is fused to a 5-7-membered heterocycle (the second ring), and the 5-7-membered heterocycle is further fused to a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycle (the third ring). In one embodiment, the second ring is a 6-membered heterocycle, and the third ring is a 6-membered heterocycle. In one embodiment, the second ring is a 7-membered heterocycle, and the third ring is a 5-membered heteroaryl.

[0120] Typically, R 2 includes 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 may be 2, 3, 4, 5, or 6. Typically, R 2 It includes at least one hydrogen bond donor (eg, OH, NH2, or NHR group) and at least one hydrogen bond acceptor (eg, C(=O) group, O, N (eg, in a pyridine ring), etc.).

[0121] In some embodiments, R 2 is a 10-membered bicyclic heteroaryl group having 1 to 4 ring nitrogen atoms, such as quinolinyl (preferably ), naphthyridinyl, etc., which are optionally substituted by one or more (e.g., 1, 2, or 3) independently selected from deuterium, halogen (e.g., F, Cl), CN, G 1 , OH, COOH, C(O)-G 1 , OG 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 , OG 2 NH(G 2 )、N(G 1 )(G 2 )、C(O)-NH(G 2 ), and C(O)-N(G 1 )(G 2 ) is substituted by a substituent,

[0122] Among them G 1 is independently at each occurrence optionally replaced by 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 1-4 Alkyl, or optionally 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 Cycloalkyl;

[0123] Among them G 2 is independently at each occurrence a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, phenyl, or a 5- or 6 membered heteroaryl, each of which is optionally substituted by 1-3 independently selected from oxo (if applicable), halo (e.g. F), CN, G 1 ,OH,OG 1 、NH2、NH(G 1 ), and N(G 1 )(G 1 ) is substituted with a substituent; and

[0124] Wherein the two optional substituents of the 10-membered bicyclic heteroaryl group, together with one or more intervening atoms, may be optionally linked to form a fused ring structure.

[0125] In some embodiments, R 2 is a 9-12 membered bicyclic heterocycle, wherein one of the two rings is a phenyl or heteroaryl ring, and R 2 The phenyl or heteroaryl rings of the bicyclic system are connected to the rest of Formula I, wherein the 9-12 membered bicyclic heterocyclic ring is optionally substituted by one or more (e.g., 1, 2 or 3) independently selected from halo (e.g., F), CN, G 1 , OH, COOH, C(O)-G 1 , OG 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 , OG 2 NH(G 2 )、N(G 1 )(G 2 )、C(O)-NH(G 2 ), and C(O)-N(G 1 )(G 2 ) is substituted by a substituent,

[0126] Among them G 1 is independently at each occurrence optionally replaced by 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 1-4 Alkyl, or optionally 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 Cycloalkyl;

[0127] Among them G 2 is independently at each occurrence a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, phenyl, or a 5- or 6 membered heteroaryl, each of which is optionally substituted by 1-3 independently selected from oxo (if applicable), halo (e.g. F), CN, G 1 ,OH,OG 1 、NH2、NH(G 1 ), and N(G 1 )(G 1 ) is substituted with a substituent; and

[0128] Wherein two optional substituents of the 9-12 membered bicyclic heterocycle together with one or more intervening atoms may be optionally linked to form a ring structure.

[0129] In some embodiments, R 2 is a 12-16 membered heteroaryl or a heterocyclic structure having three or more rings, wherein at least one of the rings is a phenyl or heteroaryl ring, and R 2 The bond to the rest of formula I is via a ring atom of the phenyl or heteroaryl portion of the ring system, for example etc., wherein the 12-16 membered heteroaryl or heterocyclic ring is optionally substituted by one or more (e.g. 1, 2 or 3) independently selected from deuterium, halogen (e.g. F, Cl), CN, G 1, OH, COOH, C(O)-G 1 , OG 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 , OG 2 NH(G 2 )、N(G 1 )(G 2 )、C(O)-NH(G 2 ), and C(O)-N(G 1 )(G 2 ) is substituted by a substituent,

[0130] Among them G 1 is independently at each occurrence optionally replaced by 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 1-4 Alkyl, or optionally 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 Cycloalkyl;

[0131] Among them G 2 is independently at each occurrence a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, phenyl, or a 5- or 6 membered heteroaryl, each of which is optionally substituted by 1-3 independently selected from oxo (if applicable), halo (e.g. F), CN, G 1 ,OH,OG 1 、NH2、NH(G 1 ), and N(G 1 )(G 1 ) is substituted with a substituent; and

[0132] Wherein two optional substituents of the 12-16 membered heteroaryl or heterocyclic ring together with one or more intervening atoms may be optionally linked to form a ring structure.

[0133] In some preferred embodiments, R in Formula I 2 It can be based on the structure of M-1:

[0134]

[0135] in:

[0136] J 1 and J 2 Independently N or CR 30 , where R 30 is independently at each occurrence hydrogen, halogen, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 heteroalkyl;

[0137] R 20 is hydrogen, halogen (such as F or Cl), CN, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 heteroalkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl);

[0138] R 21 , R 22 and R 23 are each independently: (1) hydrogen or deuterium; (2) halogen (e.g., F or Cl); (3) CN; (4) optionally substituted by 1-3 each independently of the other: F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) optionally substituted by 1-3 groups each independently being oxo, halo (eg, F), OH, NH2, C 1-4 alkyl, or C optionally substituted by F 1-4 a 3-6 membered ring structure substituted by a substituent of the heteroalkyl group (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl group),

[0139] or R 21 and R 22 Together with the intervening atoms, they form a 5-8 membered ring (e.g., a 5-7 membered carbocyclic or heterocyclic ring), which is optionally substituted with 1-3 atoms, each independently oxo, deuterium, halo (e.g., F), OH, NH2, C 1-4 alkyl, or C optionally substituted by F 1-4 The substituent of heteroalkyl is substituted, and R 23 As defined above;

[0140] or R22 and R 23 Together with the intervening atoms, they form a 5-8 membered ring (e.g., a 5-7 membered carbocyclic ring, an aryl ring, a heteroaryl ring, or a heterocyclic ring), which is optionally substituted with 1-3 atoms, each independently oxo, deuterium, halo (e.g., F), OH, NH2, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 The substituent of heteroalkyl is substituted, and R 21 As defined above.

[0141] J in M-1 1 Typically CR 30 , where R 30 As defined herein, preferably, R 30 is hydrogen. However, in some embodiments, J 1 It can be N.

[0142] J in M-1 2 Typically CR 30 , where R 30 As defined herein, preferably, R 30 is hydrogen. However, in some embodiments, J 2 It can also be N. Preferably, J 1 and J 2 Not all N.

[0143] In some preferred embodiments, J in M-1 1 and J 2 All are CH.

[0144] In one embodiment, R 2 Having a structure according to M-1-1:

[0145]

[0146] in:

[0147] R 21 , R 22 and R 23 are each independently: (1) hydrogen or deuterium; (2) halogen (e.g., F or Cl); (3) CN; (4) optionally substituted by 1-3 each independently of the other: F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) optionally substituted by 1-3 groups each independently being oxo, halo (eg, F), OH, NH2, C 1-4 alkyl, or C optionally substituted by F 1-4 The substituents of the heteroalkyl group are substituted 3-6 membered ring structures (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl).

[0148] In some embodiments, the compound having Formula I can have a structure according to Formula I-1:

[0149]

[0150] Where R 3 , R 20 , R 21 , R 22 and R 23 In some embodiments, the compound of formula I may be a deuterated analog of formula I-1, for example having a structure according to formula I-1-D:

[0151]

[0152] Where R 3 , R 20 , R 21 , R 22 and R 23 Defined in this article.

[0153] In one embodiment, R 2 Having a structure according to M-6-1:

[0154]

[0155] in:

[0156] R 20 is hydrogen, halogen (such as F or Cl), CN, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 heteroalkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl);

[0157] R 22 and R 23 are each independently: (1) hydrogen or deuterium; (2) halogen (e.g., F or Cl); (3) CN; (4) optionally substituted by 1-3 each independently of the other: F, OH, NH2, NH(C 1-4Alkyl), 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 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) optionally substituted by 1-3 groups each independently being oxo, halo (eg, F), OH, NH2, C 1-4 alkyl, or C optionally substituted by F 1-4 The substituents of the heteroalkyl group are substituted 3-6 membered ring structures (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl).

[0158] In some embodiments, R 20 is hydrogen. In some embodiments, R 20 is halogen (eg, F or Cl) or CN, such as F. In some embodiments, R 20 is C optionally substituted by F 1-4 In some embodiments, R 20 is C optionally substituted by F 1-4 Typically, C 1-4 The heteroalkyl group has 1 or 2 heteroatoms which are independently N or O. In some embodiments, R 20 It may also be an optionally substituted 3-6 membered ring structure (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl).

[0159] R 20 Typically hydrogen, halogen, or C 1-4 For example, in some preferred embodiments, R 20 R is hydrogen, F, Cl, methyl, or ethyl, more preferably F.

[0160] Preferably, R 21 , R 22 , and R 23 At least one of the R 21 , R 22 and R 23 Only one of them contains a hydrogen bond donor, or R 21 and R 22 , or R 22 and R 23 The formed ring structure contains a hydrogen bond donor.

[0161] When there is no hydrogen bond donor, R 21 , R 22 and R 23 It may typically be hydrogen, deuterium, halogen, or C which may be optionally substituted by 1 to 3 suitable substituents as defined herein. 1-4 alkyl.

[0162] In some embodiments, R 21 , R 22 and R 23 One or more of them may also be C optionally substituted by F 1-4 Heteroalkyl, wherein the heteroalkyl contains 1 or 2 heteroatoms which are independently oxygen or nitrogen.

[0163] For example, in some embodiments, R 21 Can be C 1-4 In some embodiments, R 21 It can be NH(C 1-4 Alkyl), N(C 1-3 Alkyl)(C 1-3 alkyl), where each C 1-3 Alkyl groups are independently selected provided that the total number of carbons is equal to or less than 4.

[0164] In some embodiments, R 22 Can be C 1-4 In some embodiments, R 22 It can be NH(C 1-4 Alkyl), N(C 1-3 Alkyl)(C 1-3 alkyl), where each C 1-3 Alkyl groups are independently selected provided that the total number of carbons is equal to or less than 4.

[0165] In some embodiments, R 23 Can be C 1-4 In some embodiments, R 23 It can be NH(C 1-4 Alkyl), N(C 1-3 Alkyl)(C 1-3 alkyl), where each C 1-3 Alkyl groups are independently selected provided that the total number of carbons is equal to or less than 4.

[0166] In some embodiments, R 21 , R 22 and R 23One or more of the 3-6 membered ring structures may also be substituted with 1-3 suitable substituents as defined herein (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl). For example, in some embodiments, the 3-6 membered ring structure may be unsubstituted. In some embodiments, the 3-6 membered ring structure may be substituted with 1-3 oxo, OH, halo (e.g., F), or C 1-4 For example, in some embodiments, R 21 , R 22 and R 23 One of the

[0167] In some embodiments, R 21 Can be hydrogen, deuterium, C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 In some embodiments, R 21 It can be a halogen, such as F or Cl. In some preferred embodiments, R 21 is hydrogen, deuterium, F, or methyl.

[0168] In some embodiments, R 21 Has a hydrogen bond donor. For example, in some embodiments, R 21 It can be OH, NH2, or NH(C 1-4 Alkyl) substituted C 1-4 Alkyl, preferably And in some embodiments, R 21 It can be OH, NH2, or NH(C 1-4 Alkyl) substituted C 3-4 Cycloalkyl groups, such as In such an embodiment, typically, R 22 and R 23 Nor does it have OH, NH2, or NH(C 1-4 alkyl) group, for example, in some embodiments, R 22 and R 23 Each is independently hydrogen, F, Cl, methyl, or ethyl.

[0169] In some embodiments, R 21 It may be a 4-6 membered heterocyclic ring having 1 or 2 ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc., wherein the 4-6 membered heterocyclic ring is optionally substituted by 1-3 groups each independently being oxo, F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4For example, in some embodiments, R 21 is azetidinyl or pyrrolidinyl, e.g. Typically, in such embodiments, R 22 and R 23 Not a heteroaryl or heterocyclic group.

[0170] In some embodiments, R 21 It may be a 5-membered heteroaryl ring having 2-4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., wherein the 5-membered heteroaryl ring is optionally substituted by 1-3 each independently being F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 For example, in some embodiments, R 21 is imidazolyl or pyrazolyl, which is optionally substituted by one or two C 1-4 Alkyl groups, such as methyl groups, such as Typically, in such embodiments, R 22 and R 23 Not a heteroaryl or heterocyclic group.

[0171] Various groups are also suitable for R 22 For example, in some embodiments, R 22 It can be hydrogen, C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 In some embodiments, R 22 It may be a halogen, such as F or Cl.

[0172] In some preferred embodiments, R 22 Has a hydrogen bond donor. For example, in some embodiments, R 22 It can be OH, NH2, or NH(C 1-4 Alkyl) substituted C 1-4 Alkyl, preferably And in some embodiments, R 22 It can be OH, NH2, or NH(C 1-4 Alkyl) substituted C 3-4 Cycloalkyl groups, such as In some embodiments, R 22 yes In some embodiments, R 22 It can be C substituted by NH-(3-7 membered ring) 1-4alkyl, wherein the 3-7 membered ring is preferably a 3, 4 or 5 membered ring, such as cyclopropyl. For example, in some embodiments, R 22 It can be C substituted by NH-cyclopropyl 1-4 In some embodiments, R 22 yes In some embodiments, R 22 yes In such an embodiment, typically, R 21 and R 23 Nor does it have OH, NH2, or NH(C 1-4 alkyl) group, for example, in some embodiments, R 21 and R 23 Each is independently hydrogen, deuterium, F, Cl, methyl, or ethyl.

[0173] In some embodiments, R 22 It may be a 4-6 membered heterocyclic ring having 1 or 2 ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc., wherein the 4-6 membered heterocyclic ring is optionally substituted by 1-3 groups each independently being oxo, F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 For example, in some embodiments, R 22 is azetidinyl or pyrrolidinyl, e.g. In some embodiments, R 22 is azetidinyl or pyrrolidinyl, which is optionally substituted with C 1-4 Alkyl groups, e.g. Typically, in such embodiments, R 21 and R 23 is not a heteroaryl or heterocycle. For example, in some embodiments, R 21 and R 23 Each independently is hydrogen, deuterium, F, Cl, methyl, or ethyl.

[0174] In some embodiments, R 22 It may be a 5-membered heteroaryl ring having 2-4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., wherein the 5-membered heteroaryl ring is optionally substituted by 1-3 each independently being F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 For example, in some embodiments, R 22is imidazolyl or pyrazolyl, which is optionally substituted by one or two C 1-4 Alkyl groups, such as methyl groups, such as Typically, in such embodiments, R 21 and R 23 is not a heteroaryl or heterocycle. For example, in some embodiments, R 21 and R 23 Each independently is hydrogen, deuterium, F, Cl, methyl, or ethyl.

[0175] Various groups are also suitable for R 23 For example, in some embodiments, R 23 Can be hydrogen, deuterium, C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 heteroalkyl, such as N(CH3)2. In some embodiments, R 23 It can be a halogen, such as F or Cl. In some preferred embodiments, R 23 is hydrogen, deuterium, F, Cl or methyl.

[0176] In some embodiments, R 23 Has a hydrogen bond donor. For example, in some embodiments, R 23 It can be OH, NH2, or NH(C 1-4 Alkyl) substituted C 1-4 Alkyl, preferably And in some embodiments, R 23 It can be OH, NH2, or NH(C 1-4 Alkyl) substituted C 3-4 Cycloalkyl groups, such as In such an embodiment, typically, R 21 and R 22 Nor does it have OH, NH2, or NH(C 1-4 alkyl) group, for example, in some embodiments, R 21 and R 22 Each is independently hydrogen, F, Cl, methyl, or ethyl.

[0177] In some embodiments, R 23 It may be a 4-6 membered heterocyclic ring having 1 or 2 ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc., wherein the 4-6 membered heterocyclic ring is optionally substituted by 1-3 groups each independently being oxo, F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4For example, in some embodiments, R 23 is azetidinyl or pyrrolidinyl, e.g. Typically, in such embodiments, R 21 and R 22 Not a heteroaryl or heterocyclic group.

[0178] In some embodiments, R 23 It may be a 5-membered heteroaryl ring having 2-4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., wherein the 5-membered heteroaryl ring is optionally substituted by 1-3 each independently being F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 For example, in some embodiments, R 23 is imidazolyl or pyrazolyl, which is optionally substituted by one or two C 1-4 Alkyl groups, such as methyl groups, such as Typically, in such embodiments, R 21 and R 22 Not a heteroaryl or heterocyclic group.

[0179] In some embodiments, R 21 and R 22 Together with the intervening atoms, they are linked together to form a 5- or 6-membered ring, preferably a 5- or 6-membered carbocyclic ring, which is substituted by 1-3 atoms each independently being F, OH, NH2, C 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 alkyl), preferably one of the one or more substituents comprises a hydrogen bond donor, such as OH, NH2, or NH(C 1-4 In such embodiments, R 23 Typically hydrogen, halogen (such as F or Cl), C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 Heteroalkyl.

[0180] In some embodiments, R 22 and R 23 Together with the intervening atoms, they are linked together to form a 5- or 6-membered ring, preferably a 5- or 6-membered carbocyclic ring, which is substituted by 1-3 atoms each independently being F, OH, NH2, C 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4alkyl), preferably one of the one or more substituents comprises a hydrogen bond donor, such as OH, NH2, or NH(C 1-4 In such embodiments, R 21 Typically hydrogen, halogen (such as F or Cl), C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 Heteroalkyl.

[0181] For example, in some embodiments, R 2 Can be selected from

[0182]

[0183] In some preferred embodiments, R 22 Contains a hydrogen bond donor, such as an OH, NH2, or NH group / moiety. For example, in some embodiments, R in Formula I 2 Can be selected from:

[0184]

[0185] In some preferred embodiments, R in Formula I 2 Can be selected from:

[0186]

[0187]

[0188] In some preferred embodiments, R in Formula I 2 Can be selected from:

[0189]

[0190] In some embodiments, R 21 or R 23 Contains a hydrogen bond donor, such as an OH, NH2, or NH group / moiety. For example, in some embodiments, R in Formula I 2 Can be selected from:

[0191]

[0192] In some embodiments, R in Formula I 2 It can be structured according to M-2 or M-5:

[0193]

[0194] in:

[0195] J 1 and J 2Independently N or CR 30 , where R 30 is independently at each occurrence hydrogen, halogen, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 heteroalkyl;

[0196] Ring C is a heterocyclic or heteroaryl ring, which is optionally replaced by R 110 1-5 instances of substituted, i.e., when valence permits, p is 0-5, wherein

[0197] R 110 is independently at each occurrence (1) oxo, (2) halogen (eg, F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) R 110 The two examples are linked together with one or more intervening atoms to form a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle), which is optionally substituted with 1-3 each independently being oxo, halo (e.g., F), OH, NH2, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 Substitution of heteroalkyl groups,

[0198] J 3 and J 4 N, NR independently 31 , CR 32 R 33 , or CR 34 ,in

[0199] R 31 is independently at each occurrence hydrogen, C optionally substituted with F 1-4 alkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl),

[0200] R 32 and R 33 Each of the following, at each occurrence, is independently (1) hydrogen or deuterium, (2) a halogen (e.g., F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) an optionally substituted 3-6 membered ring structure (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl); or (7) R 32 and R 33 , which are linked together with the carbon atoms to which they are commonly bonded to form a carbonyl (CO) or a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, or a 4-6 membered heterocycle), which is optionally substituted by 1-3 groups, each independently being oxo, halo (e.g., F), OH, NH2, C optionally substituted by F 1-4 alkyl, or C optionally substituted by F 1-4 Substitution of a heteroalkyl group; or

[0201] R 32 Two instances of, or R 32 An example and R 100 An example of an alkyl radical, connected together with one or more intervening atoms to form a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle), which ring structure is optionally substituted by 1-3 groups, each independently being oxo, halo (e.g., F), OH, NH2, C optionally substituted by F 1-4 alkyl, or C optionally substituted by F 1-4 Substitution of heteroalkyl groups;

[0202] R 34 is independently at each occurrence (1) hydrogen, (2) halogen (e.g., F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) an optionally substituted 3-6 membered ring structure (eg, cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl); and

[0203] R 20A and R 21A are each independently hydrogen, deuterium, halogen (such as F or Cl), CN, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 heteroalkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl).

[0204] Ring C in M-2 or M-5 can typically be a heterocyclic ring, for example, those with 1 or 2 ring heteroatoms, such as a 5- or 6-membered heterocyclic ring with 1 ring nitrogen atom, such as a tetrahydropyridine ring or a dihydropyrrole ring. In some embodiments, ring C in M-2 or M-5 can be a heteroaryl ring, such as a 5-membered heteroaryl, preferably, those with 1 or 2 ring heteroatoms, such as an imidazole or pyrazole ring. When R 110 When two instances of are joined together with one or more intervening atoms to form a 3-6 membered ring structure, Ring C together with the 3-6 membered ring structure may be a spiro, bridged or fused ring structure.

[0205] J in M-2 or M-5 1 Typically CR 30 , where R 30 As defined herein, preferably, R 30 is hydrogen. However, in some embodiments, J 1 It can be N.

[0206] J in M-2 or M-5 2 Typically CR 30 , where R 30 As defined herein, preferably, R 30 is hydrogen. However, in some embodiments, J 2 It can also be N. Preferably, J in M-2 or M-51 and J 2 Not all N.

[0207] In some preferred embodiments, J in M-2 or M-5 1 and J 2 For example, in some embodiments, the compound having Formula I can have a structure according to Formula I-2:

[0208]

[0209] Where R 3 , R 20A , R 21A , J 3 , J 4 , p, R 110 and Ring C are defined herein. In some embodiments, the compound having Formula I may be a deuterated analog having Formula I-2, for example having a structure according to Formula I-2-D:

[0210]

[0211] Where R 3 , R 20A , R 21A , J 3 , J 4 , p, R 110 and Ring C are defined herein.

[0212] In some embodiments, R 20A is hydrogen. In some embodiments, R 20A is halogen (eg, F or Cl) or CN, such as F. In some embodiments, R 20A is C optionally substituted by F 1-4 In some embodiments, R 20A is C optionally substituted by F 1-4 Typically, C 1-4 The heteroalkyl group has 1 or 2 heteroatoms which are independently N or O. In some embodiments, R 20A It may also be an optionally substituted 3-6 membered ring structure (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl).

[0213] R 20A Typically hydrogen, halogen, or C 1-4 For example, in some preferred embodiments, R 20A is hydrogen, F, Cl, methyl, or ethyl, preferably, R 20A It's F.

[0214] In some embodiments, R 21Ais hydrogen. In some embodiments, R 21A In some embodiments, R 21A is halogen (eg, F or Cl) or CN, such as F. In some embodiments, R 21A is C optionally substituted by F 1-4 In some embodiments, R 21A is C optionally substituted by F 1-4 Typically, C 1-4 The heteroalkyl group has 1 or 2 heteroatoms which are independently N or O. In some embodiments, R 21A It may also be an optionally substituted 3-6 membered ring structure (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl).

[0215] R 21A Typically 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 It is hydrogen, deuterium or methyl.

[0216] In some embodiments, the integer p is 0. In some embodiments, the integer p is 1, and R 110 It is OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 Alkyl), or C 1-4 alkyl.

[0217] In some embodiments, the integer p is 2. In such embodiments, typically, R 110 C independently at each occurrence 1-4 Alkyl (e.g. methyl, ethyl); or two R 110 With one or more intervening atoms joined together to form a 3-6 membered ring, for example a cyclopropyl ring.

[0218] In some embodiments, the integer p is 2, 3, or 4, and R 110 The two instances of are joined together with any one or more intervening atoms to form a 5- or 6-membered ring, and R 110 Any one or more of the remaining instances of are defined herein. For example, in some embodiments, R 110 Any one or more remaining non-ring-forming instances of are independently C at each occurrence 1-4 Alkyl (eg, methyl, ethyl).

[0219] J 3 and J 4 N, NR independently 31, CR 32 R 33 , or CR 34 For example, in some embodiments, J 3 YesNR 31 , and R 31 is hydrogen or C 1-4 In some embodiments, J 3 is N. In some embodiments, J 3 Yes CR 34 , and R 34 is hydrogen or C 1-4 In some embodiments, J 3 Yes CR 32 R 33 , and R 32 is hydrogen, deuterium, F, or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen, deuterium, F, or C 1-4 Alkyl (eg, methyl or ethyl), such as J 3 is CH2, CD2, CF2, CH(CH3), or C(CH3)2. In some embodiments, J 3 Yes CR 32 R 33 , and R 32 and R 33 Together with the carbon atoms to which they are simultaneously bonded, they form a 3-4 membered ring, such as cyclopropyl. 4 YesNR 31 , and R 31 is hydrogen or C 1-4 In some embodiments, J 4 is N. In some embodiments, J 4 Yes CR 34 , and R 34 is hydrogen or C 1-4 In some embodiments, J 4 Yes CR 32 R 33 , and R 32 is hydrogen, deuterium, F, or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen, deuterium, F, or C 1-4 Alkyl (eg, methyl or ethyl), such as J 4 is CH2, CD2, CF2, CH(CH3), or C(CH3)2. In some embodiments, J 4 Yes CR 32 R 33, and R 32 and R 33 Together with the carbon atoms to which they are simultaneously bonded, they form a 3-4 membered ring, such as cyclopropyl. 4 Can be C(O). Typically, when J 3 or J 4 Is N or CR 34 When, it means J 3 or J 4 Where applicable, a double bond is formed with another ring atom in Ring C, such as those exemplified herein.

[0220] In one embodiment, R 32 An example and R 100 An example of is connected together with one or more intervening atoms to form a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle) optionally substituted as described herein. 4 Yes CR 32 R 33 , and R 32 and R 100 An example of (on a ring atom, not with J 4 adjacent) to form a bridge (e.g., -NH- bridge), and R 33 is hydrogen, deuterium, F, or C 1-4 Alkyl (eg, methyl or ethyl).

[0221] For example, in some embodiments, R 2 is characterized by having a structure according to 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:

[0222]

[0223]

[0224] in:

[0225] When valence permits, p1 is 0, 1, 2, or 3; and

[0226] R 111 is hydrogen or R 110 ,and

[0227] These variables J 1 , J 2 , R 20A , R 21A , R 31 , R 32 , R 33 , R 34, and R 110 As defined herein. For example, in some embodiments, J in F-1 to F-12 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 21A are independently hydrogen, F, Cl, methyl, or ethyl. For example, in some preferred embodiments, R 20A It may 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 one or two pairs of R 32 and R 33 Together with the carbon atoms to which they are commonly bonded, they are connected to form a cyclopropyl ring. 2 is characterized by having a structure according to Formula F-1.

[0228] In one embodiment, R 2 is characterized by having a structure according to 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:

[0229]

[0230]

[0231] In some embodiments, in F-1 or F-2 (or a subformula thereof), p1 is 0, or p1 is 1, and R 110 It is C 1-4 In some embodiments, in F-1 or F-2 (or a subformula thereof), p is 2, wherein R 110 C independently at each occurrence 1-4 Alkyl (e.g. methyl, ethyl); or two R 110 With one or more intervening atoms joined together to form a 3-6 membered ring, for example a cyclopropyl ring.

[0232] In some embodiments, in F-3, F-4, F-5, F-6 or F-7 (or subformulae thereof), R 111 is hydrogen or C 1-4alkyl.

[0233] In some embodiments, in F-4, F-5, F-6, or F-7 (or subformulae thereof), R 111 is NH2 or NH(C 1-4 alkyl).

[0234] For example, in some specific embodiments, Ring C in M-2 is a heterocyclic ring, and R in Formula I 2 Can be selected from:

[0235] In some specific embodiments, Ring C in M-2 is a heterocyclic ring, and R in Formula I 2 Can be selected from:

[0236]

[0237] In some specific embodiments, Ring C in M-2 is a 5-membered heterocyclic ring or a heteroaryl ring, and R in Formula I 2 Can be selected from:

[0238]

[0239] In some specific embodiments, ring C and R in M-2 110 Two instances of are linked together to form a bridged heterocycle, for example, R in Formula I 2 Can be

[0240] In some embodiments, R in Formula I 2 It can be a structure according to M-3 or M-4:

[0241]

[0242] in:

[0243] J 1 and J 2 Independently N or CR 30 , where R 30 is independently at each occurrence hydrogen, halogen, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 heteroalkyl;

[0244] Ring C is a heterocyclic or heteroaryl ring, which is optionally replaced by R 110 1-5 instances of substituted, i.e., when valence permits, p is 0-5, wherein

[0245] R 110 is independently at each occurrence (1) oxo, (2) halogen (eg, F or Cl), (3) OH, NH2, NH(C1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) R 110 The two examples are linked together with one or more intervening atoms to form a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle), which is optionally substituted with 1-3 each independently being oxo, halo (e.g., F), OH, NH2, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 Substitution of heteroalkyl groups,

[0246] U is O or C(=O);

[0247] W and V are independently C, N, or CR 34 ;

[0248] t is 0, 1, 2, or 3, and each Z is independently O, N, NR 31 , CR 32 R 33 , or CR 34 ;

[0249] wherein the bond between W and V, W and Z, or two consecutive Zs is a single bond or a double bond when valence permits,

[0250] J 3 and J 4 N, NR independently 31 , CR 32 R 33 , or CR 34 ,in

[0251] R 31 is independently at each occurrence hydrogen, C optionally substituted with F 1-4 alkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl),

[0252] R32 and R 33 Each of the following, at each occurrence, is independently (1) hydrogen, (2) halogen (e.g., F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) an optionally substituted 3-6 membered ring structure (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl); or (7) R 32 and R 33 , which are linked together with the carbon atoms to which they are commonly bonded to form a carbonyl (CO) or a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, or a 4-6 membered heterocycle), which is optionally substituted by 1-3 groups, each independently being oxo, halo (e.g., F), OH, NH2, C optionally substituted by F 1-4 alkyl, or C optionally substituted by F 1-4 Substitution of heteroalkyl groups;

[0253] R 34 is independently at each occurrence (1) hydrogen, (2) halogen (e.g., F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4heteroalkyl, or (6) an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl);

[0254] or J 3 and R 110 An instance of J 4 and R 110 An instance of is linked together with one or more intervening atoms to form a ring structure;

[0255] R 20A is hydrogen, halogen (such as F or Cl), CN, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 heteroalkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl); and

[0256] R 22A and R 23A are each independently: (1) hydrogen; (2) halogen (e.g., F or Cl); (3) CN; (4) optionally substituted by 1 to 3 each independently of the other: F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) optionally substituted by 1-3 groups each independently being oxo, halo (eg, F), OH, NH2, C 1-4 alkyl, optionally substituted with F 1-4 The substituents of the heteroalkyl group are substituted 3-6 membered ring structures (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl).

[0257] Ring C in M-3 can typically be a heterocyclic ring, for example, those with 1 or 2 ring heteroatoms, such as a 5- or 6-membered heterocyclic ring with 1 ring nitrogen atom, such as a tetrahydropyridine ring or a dihydropyrrole ring. In some embodiments, ring C in M-3 can be a heteroaryl ring, such as a 5-membered heteroaryl, preferably, those with 1 or 2 ring heteroatoms, such as an imidazole or pyrazole ring.

[0258] When valence permits, the bond between W and V is a single bond or a double bond. Similarly, when valence permits, the bond between W and Z is a single bond or a double bond. And when valence permits, two consecutive Zs can be connected by a single bond or a double bond.

[0259] J in M-3 or M-4 1 Typically CR 30 , where R 30 As defined herein, preferably, R 30 is hydrogen. However, in some embodiments, J 1 It can be N.

[0260] J in M-3 or M-4 2 Typically CR 30 , where R 30 As defined herein, preferably, R 30 is hydrogen. However, in some embodiments, J 2 It can also be N. Preferably, J in M-3 or M-4 1 and J 2 Not all N.

[0261] In some preferred embodiments, J in M-3 or M-4 1 and J 2 For example, in some embodiments, the compound having formula I can have a structure according to formula I-3 or I-4:

[0262]

[0263] Where R 3 , R 20A , R 22A , R 23A , J 3 , J 4 , p, R 110 , T, U, V, W, Z and Ring C are defined herein.

[0264] In some embodiments, R 20A is hydrogen. In some embodiments, R 20A is halogen (eg, F or Cl) or CN, such as F. In some embodiments, R 20A is C optionally substituted by F 1-4 In some embodiments, R 20A is C optionally substituted by F 1-4 Typically, C 1-4 The heteroalkyl group has 1 or 2 heteroatoms which are independently N or O. In some embodiments, R 20AIt may also be an optionally substituted 3-6 membered ring structure (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl).

[0265] R 20A Typically hydrogen, halogen, or C 1-4 For example, in some preferred embodiments, R 20A is hydrogen, F, Cl, methyl, or ethyl.

[0266] In some embodiments, the integer p is 0. In some embodiments, the integer p is 1, and R 110 It is OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 Alkyl), or C 1-4 alkyl.

[0267] In some embodiments, the integer p is 2. In such embodiments, typically, R 110 C independently at each occurrence 1-4 Alkyl (e.g. methyl, ethyl); or two R 110 With one or more intervening atoms joined together to form a 3-6 membered ring, for example a cyclopropyl ring.

[0268] J 3 and J 4 N, NR independently 31 , CR 32 R 33 , or CR 34 For example, in some embodiments, J 3 YesNR 31 , and R 31 is hydrogen or C 1-4 In some embodiments, J 3 is N. In some embodiments, J 3 Yes CR 34 , and R 34 is hydrogen or C 1-4 In some embodiments, J 3 Yes CR 32 R 33 , and R 32 is hydrogen or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl), such as J 3 is CH2, CH(CH3), or C(CH3)2. In some embodiments, J 3 Yes CR 32R 33 , and R 32 and R 33 Together with the carbon atoms to which they are simultaneously bonded, they form a 3-4 membered ring, such as cyclopropyl. 4 YesNR 31 , and R 31 is hydrogen or C 1-4 In some embodiments, J 4 is N. In some embodiments, J 4 Yes CR 34 , and R 34 is hydrogen or C 1-4 In some embodiments, J 4 Yes CR 32 R 33 , and R 32 is hydrogen or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl), such as J 4 is CH2, CH(CH3), or C(CH3)2. In some embodiments, J 4 Yes CR 32 R 33 , and R 32 and R 33 Together with the carbon atoms to which they are simultaneously bonded, they form a 3-4 membered ring, such as cyclopropyl. 3 or J 4 Is N or CR 34 When, it means J 3 or J 4 Each forms a double bond with another ring atom in ring C, such as those exemplified herein.

[0269] U in M-3 or M-4 is usually O. In some embodiments, U may also be C(=O).

[0270] The integer t is usually 1 or 2.

[0271] Typically, Z is independently CR at each occurrence. 32 R 33 , and R 32 is hydrogen or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl), for example, Z is CH2, CH(CH3), or C(CH3)2. In some embodiments, an example of Z is CR 32 R 33, where R 32 and R 33 Together with the carbon atoms to which they are simultaneously bonded, to form a 3-4 membered ring, such as cyclopropyl; and any remaining instances of Z are independently CR 32 R 33 , where R 32 is hydrogen or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl), for example, the remaining instances of Z are independently CH2, CH(CH3), or C(CH3)2.

[0272] In some embodiments, W is C, and Z directly connected to W is CR 34 , where R 34 is hydrogen or C 1-4 An alkyl group (eg, methyl or ethyl) and the bond between Z and W is a double bond.

[0273] In some embodiments, W is C. In some embodiments, W is CH.

[0274] In some embodiments, V is C. In some embodiments, V is CH. In some embodiments, V is N.

[0275] For example, in some embodiments, M-3 or M-4 may have the following structure:

[0276]

[0277] These variables are defined herein.

[0278] In one embodiment, R 2 Having a structure according to 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:

[0279]

[0280]

[0281] in:

[0282] R 111 is hydrogen or R 110 (where R 110 as defined herein or elsewhere).

[0283] R in M-4 22A It can be typically hydrogen, C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen1-4 For example, in some embodiments, R 22A It may be hydrogen or methyl.

[0284] In some embodiments, R in M-4 (eg, M-4-D) 22A It can be OH, NH2, or NH(C 1-4 Alkyl) substituted C 1-4 Alkyl groups, for example,

[0285] R in M-4 23A It can be typically hydrogen, C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 For example, in some embodiments, R 23A It may be hydrogen or methyl.

[0286] In some embodiments, R in M-4 23A It can be OH, NH2, or NH(C 1-4 Alkyl) substituted C 1-4 alkyl.

[0287] In some embodiments, R 22A and R 23A One of the groups is a group containing a hydrogen bond donor.

[0288] In some specific embodiments, Ring C in M-3 is a 5-membered heteroaryl, and R 2 Can be selected from:

[0289]

[0290] In some specific embodiments, Ring C in M-3 is a heterocyclic structure, and R 2 Can be selected from:

[0291]

[0292] In some preferred embodiments, R 2 Can be selected from

[0293]

[0294] A variety of groups are suitable for 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 It is C(O)NR 11R 12 , where R 11 and R 12 In this paper, it is defined that, for example, R 11 and R 12 In some embodiments, R 3 is 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.

[0295] In any embodiment herein, unless specified or otherwise contradicted by context, R in Formula I (or any subformula provided herein, such as 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 3 It can be hydrogen, F, Cl, Br, C optionally substituted by F 1-4 Alkyl, or CN.

[0296] In some embodiments, R in Formula I (or any applicable subformula as described herein, such as 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 3 It may be optionally substituted C 1-4 In some embodiments, R 3 can be optionally substituted by one or more, for example 1-3 independently selected from deuterium, F, CN, or OR C Substituents substituted with C 1-4 Alkyl, where R C is optionally replaced by 1-3 independently selected from deuterium, F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 1-4 alkyl, or optionally substituted by 1-3 independently selected from deuterium, F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 For example, in some embodiments, R 3 It can be methyl, CD3, CH2-OMe, CH2-OCD3, ethyl, CHF2, CF2CH3, CH2CH2F, CH2CF2H, or CF3. In some embodiments, R 3It can be CF2CF3. In some preferred embodiments, R 3 It can be F or Cl.

[0297] In some embodiments, R in Formula I (or any applicable subformula as described herein, such as 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 3 It may be optionally substituted C 2-4 Alkenyl, e.g.

[0298] In some embodiments, R in Formula I (or any applicable subformula as described herein, such as 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 3 It may be optionally substituted C 2-4 Alkynyl, e.g.

[0299] In some embodiments, R in Formula I (or any applicable subformula as described herein, such as 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 3 It can be OR A For example, in some embodiments, R 3 Yes OR A , and R A is hydrogen, optionally substituted by 1-3 independently selected from deuterium, F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 1-4 alkyl, or optionally substituted by 1-3 independently selected from deuterium, F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 Cycloalkyl.

[0300] In some embodiments, R in Formula I (or any applicable subformula as described herein, such as 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 3 Can be C(O)R B For example, in some embodiments, R 3 It is C(O)R B And R B is hydrogen, optionally substituted by 1-3 independently selected from deuterium, F, CN, OH, and C1-4 Substituents of heteroalkyl substituted C 1-4 alkyl, or optionally substituted by 1-3 independently selected from deuterium, F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 Cycloalkyl.

[0301] In some embodiments, R 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, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) is 3 It can also be C 3-6 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 is optionally substituted by 1-3 independently selected from 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 ) is substituted by a substituent, wherein G 1 is optionally replaced by 1-3 independently selected from deuterium, F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 1-4 alkyl, or optionally substituted by 1-3 independently selected from deuterium, F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 Cycloalkyl.

[0302] In any embodiment herein, unless specified or otherwise contradicted by context, R 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, A-2, I-1, I-1-D, I-2, I-2-D, I-3, or I-4) is 3 Can be selected from:

[0303]

[0304] R in Formula I (or any applicable subformula as described herein, such as 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 4 Typically, it is hydrogen. In some embodiments, R 4 In some embodiments, R in Formula I 4 It may also be halogen (eg, F), optionally substituted C 1-6 Alkyl, or NR 11 R 12 For example, in some embodiments, R in Formula I 4 It's NH2.

[0305] In some embodiments, 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 , together with these intervening atoms, may also be connected to form an optionally substituted 4-8 membered ring structure, such as a 4-8 membered heterocyclic structure or a 5 or 6 membered heteroaryl structure. For example, in any embodiment herein, unless specified or otherwise contrary to the context, in Formula I (or any applicable subformula as described herein, such as Formula IA, IB, A, A-S1, A-S2, A-S3, A-S4, A-1, or A-2), R 3 and R 4 Together with the inserted atoms can connect to form one of the following:

[0306]

[0307] 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 The alkyl group is optionally substituted by 1-3 groups each independently of the other: F, OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl) substituent.

[0308] In some embodiments, the present disclosure also provides a compound selected from the following Table 1, a deuterated analog thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0309] Table 1. List of compounds

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331] The compounds of Table 1 may exist in a variety of stereoisomeric forms, such as individual isomers, individual enantiomers and / or diastereomers (if applicable), or stereoisomer mixtures (including racemic mixtures and mixtures enriched in one or more stereoisomers). In some embodiments, when applicable, the compounds shown in Table 1 may have an enantiomeric excess ("ee") greater than 60%, such as 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 other enantiomers with undetectable amounts. In some embodiments, when applicable, the compounds shown in Table 1 may also exist as a mixture of stereoisomers (in any ratio), such as a racemic mixture.

[0332] In some embodiments, the compound classes described herein also exclude any specific known single compounds prior to the present disclosure, to the extent applicable. In some embodiments, any subclass or compound species that fully belonged to the compound classes described herein prior to the present disclosure may also be excluded from this class of compounds herein, to the extent applicable.

[0333] Given this disclosure, one skilled in the art can readily synthesize the compounds disclosed herein. Exemplary syntheses are also shown in the Examples section.

[0334] As will be clear to those skilled in the art, conventional protecting groups are necessary to protect certain functional groups from being subjected to undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in "Protective Groups in Organic Synthesis", 4th edition PGM Wuts; TW Greene, John Wiley, 2007, and references cited therein. The reagents used for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many reagents are available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA). Other reagents can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supplements (Elsevier Science Publishers, 1989); Organic Reactions, vols. 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (Wiley, 7th ed.); and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), or any updated version available up to the time of this application.

[0335] Pharmaceutical composition

[0336] Certain embodiments relate to pharmaceutical compositions comprising one or more compounds of the disclosure.

[0337] The pharmaceutical composition may optionally include a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition includes a compound of the present disclosure (e.g., a compound having Formula I (or any subformula provided by the text, 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), any one of Examples 1-111, or any specific compound 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 suitable excipients include, for example, encapsulating materials or additives, such as antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavoring agents, wetting agents, lubricants, fragrances, preservatives, propellants, anti-adherents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st ed., A. R. Gennaro (Lippincott, Baltimore, Maryland, Williams & Wilkins Publishing Company, 2005; incorporated herein by reference), which discloses various excipients for formulating pharmaceutical compositions and known techniques for preparing pharmaceutical compositions.

[0338] The pharmaceutical composition may include any one or more compounds disclosed herein. For example, in some embodiments, the pharmaceutical composition includes, for example, a therapeutically effective amount of a compound having Formula I (or any subformula provided in the text, for example, 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), any one of Examples 1-111, or any specific compound disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof. In any embodiment described herein, the pharmaceutical composition may include a therapeutically effective amount (for example, for the treatment of breast cancer or ovarian cancer) of a compound selected from any one of Examples 1-111, or any specific compound disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the pharmaceutical composition may include a compound selected from compounds according to Examples 1-111, which have a CDK4 / Cyclin D1 IC50 level designated as "A" or "B" in Table 2 herein, preferably "A".

[0339] The pharmaceutical compositions herein may be formulated for delivery by any known delivery route, including but not limited to oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral administration.

[0340] In some embodiments, the pharmaceutical composition can be formulated for oral administration. Oral formulations can be present as discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for preparing compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, 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, groundnut oil, hydroxypropyl methylcellulose, isopropyl alcohol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, oil), potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactant, talc, tragacanth, tetrahydrofurfuryl alcohol, triglyceride, water and mixtures thereof.

[0341] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., 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 suitable excipients include, for example, 1,3-butylene glycol, 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.

[0342] The compounds of the present disclosure can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, for example, in combination with additional anti-cancer therapeutic agents, such as mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormone agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as protein tyrosine kinase and / or serine / threonine kinase inhibitors, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immuno-oncology agents, etc. In some embodiments, one or more compounds of the present disclosure can be used in combination with one or more targeting agents, such as 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 inhibitors, or immunomodulators, such as PD-1 or PD-L1 antagonists, OX40 agonists or 4-1BB agonists. In some embodiments, one or more compounds of the present disclosure can be used in combination with standard therapeutic agents, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole or trastuzumab. Suitable additional anticancer therapeutic agents include any of those known in the art, such as those approved by regulatory agencies such as the U.S. Food and Drug Administration for use in suitable cancers. Some examples of suitable additional anticancer therapeutic agents also include those described as suitable for use in combination with CDK inhibitors in WO 2019 / 207463, WO2020 / 224568, etc., the contents of each of which are incorporated herein by reference in their entirety.

[0343] When used in combination with one or more additional therapeutic agents, the compounds of the disclosure or the pharmaceutical compositions herein can be administered to a subject simultaneously or sequentially with such additional therapeutic agents in any order. In some embodiments, the pharmaceutical composition can include one or more compounds of the disclosure and one or more additional therapeutic agents in a single composition. In some embodiments, the pharmaceutical composition comprising one or more compounds of the disclosure can be included in a kit that also includes a separate pharmaceutical composition comprising one or more additional therapeutic agents.

[0344] The pharmaceutical composition may include various amounts of the compounds of the present disclosure, depending on various factors, such as the intended use of the compound and the efficacy and selectivity. In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compounds of the present disclosure. In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compounds of the present disclosure and a pharmaceutically acceptable excipient. As used herein, the therapeutically effective amount of the compounds of the present disclosure is an amount that effectively treats a disease or disorder 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 treatment, the efficacy of the compound, its clearance rate, and whether another drug is administered simultaneously.

[0345] Treatment / Use

[0346] The compounds disclosed herein have a variety of uses. For example, the compounds disclosed herein can be used as therapeutically active substances for treating and / or preventing CDK4-mediated diseases or disorders. Accordingly, some embodiments of the disclosure also relate to methods of using one or more compounds disclosed herein or the pharmaceutical compositions herein to treat or prevent CDK4-mediated diseases or disorders in subjects in need thereof, such as methods of treating cancer in subjects in need thereof.

[0347] In some embodiments, the disclosure provides a method of inhibiting abnormal cell growth in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutical composition described herein. In some embodiments, the abnormal cell growth is a cancer associated with CDK4.

[0348] In some embodiments, the disclosure also provides a method of inhibiting CDK activity in a subject or biological sample. In some embodiments, the disclosure provides a method of inhibiting CDK4 activity in a subject or biological sample, the method comprising contacting the subject or biological sample with an effective amount of a compound of the disclosure (e.g., a compound having Formula I (or any subformula provided in the text, 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), any one of Examples 1-111, or any specific compound disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein.

[0349] In some embodiments, the disclosure provides a method for treating or preventing a CDK-mediated, particularly 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 disclosure (e.g., a compound having 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), any one of Examples 1-111, or any specific compound disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, a CDK4-mediated disease or disorder is, for example, a cancer described herein.

[0350] In some embodiments, the disclosure also provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound having 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), any one of Examples 1-111, or any specific compound 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 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.

[0351] 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 primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer can be advanced or metastatic breast cancer.

[0352] In some embodiments of the methods herein, the cancer is ovarian cancer.

[0353] In some embodiments, the compound of this disclosure is used as a first-line therapy. In other embodiments, the compound of this disclosure is used as a second-line (or later) therapy. In some embodiments, after treatment with endocrine therapy agents and / or CDK4 / CDK6 inhibitors, the compound of this disclosure is used as a second-line (or later) therapy. In some embodiments, after treatment with endocrine therapy agents, such as aromatase inhibitors, SERMs or SERDs, the compound of this disclosure is used as a second-line (or later) therapy. In some embodiments, after treatment with CDK4 / CDK6 inhibitors, the compound of this disclosure is used as a second-line (or later) therapy. In some embodiments, after treatment with one or more chemotherapy regimens, including taxanes or platinum agents, the compound of this disclosure is used as a second-line (or later) therapy. In some embodiments, after treatment with HER2 targeting agents, such as trastuzumab, the compound of this disclosure is used as a second-line (or later) therapy.

[0354] In some embodiments, the disclosure also provides a method of treating breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound having 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), any one of Examples 1-111, or any specific compound 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 primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

[0355] In some preferred embodiments, the compounds of the present disclosure used in the methods herein have a CDK4 / Cyclin D1 IC50 of less than 100 nM, more preferably less than 10 nM, measured / calculated according to Biological Example 1 herein. In some preferred embodiments, the compounds of the present disclosure used in the methods herein are selected from compounds according to Examples 1-111, which have a CDK4 / Cyclin D1 IC50 level designated as "A" or "B", preferably "A" in Table 2 herein.

[0356] In some preferred embodiments, the compounds disclosed herein for use in the methods herein are selective for CDK4 over CDK6. In some embodiments, the compounds disclosed herein for use in the methods herein may also be selective for CDK4 over other CDKs.

[0357] In some embodiments, the present disclosure provides a method of inhibiting the proliferation of cancer cells in a subject, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof in an amount effective to inhibit cell proliferation.

[0358] In some embodiments, the present disclosure provides a method of inhibiting cancer cell invasion in a subject, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof in an amount effective to inhibit cell invasion.

[0359] In some embodiments, the present disclosure provides a method of inducing apoptosis in cancer cells in a subject, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof in an amount effective to induce apoptosis.

[0360] In some embodiments, the present disclosure provides a method of inhibiting metastasis of cancer cells in a subject, the method 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.

[0361] Administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the 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.

[0362] The compounds disclosed herein can be used as monotherapy or in combination therapy. In some embodiments according to the methods described herein, one or more compounds disclosed herein can be used as only one or more active ingredients. In some embodiments according to the methods described herein, one or more compounds disclosed herein can also be co-administered with another therapeutic agent, and co-administered to a subject in need simultaneously or in any order. Another therapeutic agent can generally be another anticancer therapeutic agent, such as a mitotic inhibitor, an alkylating agent, an antimetabolite, an antitumor antibiotic, an antiangiogenic agent, a topoisomerase I and II inhibitor, a plant alkaloid, a hormone agent and an antagonist, a growth factor inhibitor, radiation, a signal transduction inhibitor, such as a protein tyrosine kinase and / or a serine / threonine kinase inhibitor, a cell cycle inhibitor, a biological response modifier, an enzyme inhibitor, an antisense oligonucleotide or an oligonucleotide derivative, a cytotoxic agent, an immuno-oncology agent, etc. In some embodiments, another anticancer 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 can be administered in combination with one or more targeting agents, such as 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 inhibitors, or immunomodulators, such as PD-1 or PD-L1 antagonists, OX40 agonists or 4-1BB agonists. In some embodiments, one or more compounds of the present disclosure can be administered in combination with standard therapeutic agents, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole or trastuzumab. Suitable additional anticancer therapeutic agents include any of those known in the art, such as those approved by regulatory agencies such as the U.S. Food and Drug Administration for use in suitable cancers. Some examples of suitable additional anticancer 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 entirety.

[0363] Dosage regimens, including dosages of the methods described herein, can be varied and adjusted and can depend on the recipient of treatment, the disorder, condition or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is being administered simultaneously.

[0364] definition

[0365] It is to be understood that all moieties and combinations thereof retain appropriate valences.

[0366] It should also be understood that a specific embodiment of a variable portion herein may be the same as or different from another specific embodiment having the same identifier.

[0367] Suitable groups for the variables in the compounds of Formula I or its subformulae are independently selected. Non-limiting useful groups for the variables in the compounds of Formula I or its subformulae (if applicable) include any corresponding groups as shown in the Examples or in the specific compounds described in Table 1 herein, alone or in any combination. 1 For example, in some embodiments, the compound having Formula I may include any R shown in the examples or in the specific compounds described in Table 1 herein. 1 R 1 In some embodiments, compounds having Formula I may include any of the R groups shown in the examples or in the specific compounds described in Table 1 herein. 1 R 1 The group and at least one other variable (e.g., L) according to the examples or specific compounds described in Table 1 herein. 1 ) where R 1 and at least one other variable may be derived from the same compound or from different compounds. Any such combinations are contemplated and are within the scope of the present disclosure. Unless otherwise indicated, a description of a variable associated with a formula also applies to any other overlapping formulas (e.g., subformulas) in which the variable is present.

[0368] The embodiments of the present disclosure described may be combined. Such combinations are contemplated and are within the scope of the present disclosure. For example, if applicable, it is contemplated that L of Formula I (or any subformula provided herein, such as 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 combined. 1 , R 1 , R 2 , R 3 , R 4 and any one or more of X is defined in the same way as L 1 , R 1 , R 2 , R 3 , R 4 and any one or more of the definitions in X, and the compounds resulting from the combination are within the scope of the present disclosure.

[0369] symbol Shown as perpendicular to or otherwise crossing the bonds, e.g. Indicates the point of attachment of the moiety shown to the rest of the molecule. It should be noted that one or more groups directly attached may be shown in the symbol In addition, to indicate connectivity, as understood by those skilled in the art.

[0370] Definitions of specific functional groups and chemical terms are described in more detail below.The chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th ed., 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, 3rd ed., Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way to the exemplary list of substituents described herein.

[0371] The compounds described herein may contain one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, and may be in the form of stereoisomer mixtures (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., 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, New York, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, Indiana, 1972). The present disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers, including racemic mixtures. When stereochemistry is specifically drawn, unless otherwise contradictory by context, it is understood that, with respect to that particular chiral center or axial chirality, the compound may exist primarily as the drawn stereoisomer, e.g., less than 20%, less than 10%, less than 5%, less than 1% by weight by HPLC or SFC area or both, or with undetectable amounts of one or more other stereoisomers. For example, in some embodiments, the compound may exist primarily as a drawn stereoisomer with an enantiomeric excess ("ee") greater than 80%, e.g., with an ee of 90% or more, 95% or more, 98% or more, 99% or more, or with undetectable amounts of another enantiomer. The presence and / or amount of stereoisomers can be determined by one skilled in the art in light of the present disclosure, including by using chiral HPLC or chiral SFC.As will be understood by those skilled in the art, when "*" is shown in the chemical structures herein, unless otherwise indicated by the context, it indicates that the corresponding chiral center is enantiomerically pure or enriched in either configuration or is enantiomerically pure or enriched in the drawn configuration, for example, less than 20%, less than 10%, less than 5%, less than 1% by weight, or with undetectable amounts of other one or more stereoisomers by HPLC or SFC area or both. In addition, when stereochemistry is not specifically drawn and "*" is not used in the chemical structure, unless otherwise indicated by the context, it should be understood that such a structure includes the corresponding compound in any stereoisomeric form, including individual isomers substantially free of other isomers, and mixtures of various isomers, including racemic mixtures.

[0372] When a numerical range is listed, it is intended to include every value and sub-range within that range. For example, "C 1–6 " is intended to cover C1, C2, C3, C4, C5, C6, C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 and C 5–6 .

[0373] As used herein, the term "one or more compounds of the present disclosure" refers to any compound described herein according to Formula I (or any subformula provided herein, for example, 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), any of Examples 1-111, or any specific compound disclosed in Table 1 herein, and one or more isotopically labeled compounds thereof (e.g., deuterated Analogs in which one or more hydrogen atoms are replaced by deuterium atoms having an abundance higher than its natural abundance, for example, CD3 analogs when the compound has a CH3 group), possible regioisomers, possible geometric isomers, possible stereoisomers (including diastereomers, enantiomers and racemic mixtures), tautomers, conformational isomers, pharmaceutically acceptable esters and / or possible pharmaceutically acceptable salts thereof (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 the compounds in the Examples section, marked only with integers, or marked with integers followed by "a", "b", etc. to indicate different stereoisomers of the compounds marked with integers, such as 1, 2, etc., 15a, 15b, up to 111a and 111b. See, for example, Examples 1-27 herein. Hydrates and solvates of the compounds disclosed herein are considered to be compositions of the disclosure in which one or more compounds are associated with water or a solvent, respectively. In some embodiments, the compounds of the present disclosure may be any of those according to the claims provided herein.

[0374] The compounds of the present disclosure may exist in isotopically labeled or isotopically enriched form, containing one or more atoms with an atomic mass or mass number different from the atomic mass or mass number found most abundantly in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 32 P. 35 S. 18 F. 36 Cl, and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of the invention.

[0375] As used herein, the phrases "administration of" a compound, "administering" a compound, or other variations thereof, refers to providing a compound or a prodrug of a compound to a subject in need of treatment.

[0376] As used herein, the term "alkyl" used alone or as part of another group refers to a straight or branched aliphatic saturated hydrocarbon. In some embodiments, the alkyl group may include one to twelve carbon atoms (i.e., C 1-12 In one embodiment, the alkyl group is 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 Alkyl groups. For example, C 1-4 Alkyl groups include methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl and isobutyl. As used herein, the term "alkylene" used alone or as part of another group refers to a divalent group derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, etc. Unless otherwise indicated, an alkyl group is optionally substituted.

[0377] As used herein, the term "alkenyl" used alone or as part of another group refers to a straight or branched aliphatic hydrocarbon containing one or more, for example one, two or three, carbon-carbon double bonds. In one embodiment, the alkenyl group is C 2-6 In another embodiment, the alkenyl group is C 2-4 Alkenyl groups. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl and hexenyl. Unless otherwise indicated, alkenyl groups are optionally substituted.

[0378] As used herein, the term "alkynyl" used alone or as part of another group refers to a straight or branched aliphatic hydrocarbon containing one or more, for example, one to three, carbon-carbon triple bonds. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In one embodiment, the 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, butynyl, 2-butynyl, pentynyl, and hexynyl groups. Unless otherwise indicated, alkynyl groups are optionally substituted.

[0379] As used herein, the term "alkoxy" used alone or as part of another group refers to a radical having the formula OR a1 A group in which R a1 is an alkyl group as described herein.

[0380] As used herein, the term "cycloalkoxy" used alone or as part of another group refers to a cycloalkoxy radical having the formula OR a1 A group in which R a1 is a cycloalkyl group as described herein.

[0381] As used herein, the term "haloalkyl" used alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In a preferred embodiment, a haloalkyl group is an alkyl group substituted with one, two or three fluorine atoms. In one embodiment, the haloalkyl group is C 1-10 In one embodiment, the haloalkyl group is C 1-6 In one embodiment, the haloalkyl group is C 1-4 A haloalkyl group.

[0382] As used herein, the term "heteroalkyl", alone or in combination with another term, unless otherwise indicated, refers to a stable straight or branched chain alkyl group, for example, having 2 to 14 carbons, for example 2 to 10 carbons in the chain, one or more of which has been replaced by a heteroatom selected from S, O, P and N, and wherein the nitrogen, phosphine and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms S, O, P and N may be located at any interior position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. When a heteroalkyl group is referred to as being substituted, one or more substituents may replace one or more hydrogen atoms attached to one or more carbon atoms and / or one or more heteroatoms of the heteroalkyl group. In some embodiments, the heteroalkyl group is C 1-4 Heteroalkyl refers to a heteroalkyl group having 1 to 4 carbon atoms as defined herein. 1-4 Examples of heteroalkyl groups include, but are not limited to, C4 heteroalkyl groups, such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl groups, such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, C2 heteroalkyl groups, such as -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3, and C1 heteroalkyl groups, such as -CH2-OH, -CH2-NH2, -O-CH3. In any embodiments described herein, C 1-4The heteroalkyl group preferably has 1 or 2 heteroatoms, such as those having one oxygen atom, one oxygen and one nitrogen atom, two oxygen atoms or two nitrogen atoms. Similarly, the term "heteroalkylene" by itself or as part of another substituent refers to a divalent group derived from a heteroalkyl group, such as, but not limited to -CH2-CH2-O-CH2-CH2- and -O-CH2-CH2-NH-CH2-. For heteroalkylene, heteroatoms may also occupy one or both chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). In addition, for alkylene and heteroalkylene linking groups, the direction of writing of the linking group formula does not imply the direction of the linking group. When "heteroalkylene" is listed, and then a specific heteroalkyl group, such as -NR'R", etc., is listed, it should be understood that the terms heteroalkylene and -NR'R" are not redundant or mutually exclusive. Instead, specific heteroalkyl groups are listed to increase clarity. Therefore, the term "heteroalkylene" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R", etc. Unless otherwise indicated, the heteroalkyl group is optionally substituted.

[0383] "Carbocyclyl" or "carbocyclic" used alone or as part of another group refers to a ring having at least 3 carbon atoms, for example 3 to 10 ring carbon atoms ("C 3–10 The term "carbocyclyl" refers to a group of non-aromatic cyclic hydrocarbon groups having zero heteroatoms in the non-aromatic ring system. The carbocyclyl group may be a monocyclic ring (a "monocyclic carbocyclyl") or contain a fused, bridged or spiro ring system, such as a bicyclic ring system (a "bicyclic carbocyclyl"), and may be saturated or may be 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" used alone or as part of another group refers to a divalent radical derived from a carbocyclyl group as defined herein. Unless otherwise indicated, the carbocyclyl group is optionally substituted.

[0384] In some embodiments, a "carbocyclyl" is fully saturated, which is also referred to as a cycloalkyl. In some embodiments, a cycloalkyl may have 3 to 10 ring carbon atoms ("C 3-10 In preferred embodiments, the cycloalkyl group is a monocyclic ring. As used herein, the term "cycloalkylene" used alone or as part of another group refers to a group derived from a cycloalkyl group, such as Etc. divalent groups.

[0385] "Heterocyclyl" or "heterocyclic" used alone or as part of another group refers to a group of a 3- or larger (e.g., 3- to 14-membered) non-aromatic ring system having ring carbon atoms and at least one ring heteroatom (e.g., 1 to 4 ring heteroatoms), wherein each heteroatom is 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 a carbon atom or a nitrogen atom, where valence permits. The heterocyclyl group may be a monocyclic ("monocyclic heterocyclyl") or a fused, bridged, or spirocyclic system, such as a bicyclic system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. The heterocyclyl bicyclic system 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" used alone or as part of another group refers to a divalent group derived from a heterocyclyl group defined herein. A heterocyclyl or heterocyclylene group may be optionally connected to the rest of the molecule via a carbon or nitrogen atom. Unless otherwise specified, heterocyclyl groups are optionally substituted.

[0386] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thiranyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiofuranyl, dithiofuranyl, 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, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiocanyl. 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 5,6-bicyclic heterocycles) include, but are not limited to, dihydroindole, isoindolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0387] "Aryl" used alone or as part of another group refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10 or 14 π electrons in the cyclic array) radical, for example, the aromatic ring system provides 6-14 ring carbon atoms and zero heteroatoms ("C 6–14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 As used herein, the term "arylene" used alone or as part of another group refers to a divalent radical derived from an aryl group as defined herein. Unless otherwise indicated, an aryl group is optionally substituted.

[0388] "Aralkyl" used alone or as part of another group refers to an alkyl group substituted with one or more aryl groups, preferably substituted with one aryl group. Examples of aralkyl groups include benzyl, phenethyl, etc. Unless otherwise indicated, aralkyl groups are optionally substituted. When aralkyl is referred to as optionally substituted, either the alkyl portion or the aryl portion of the aralkyl group may be optionally substituted.

[0389] "Heteroaryl" used alone or as part of another group refers to a monocyclic, bicyclic or tricyclic 4n+2 aromatic ring system (e.g., sharing 6 or 10 π electrons in a cyclic array) group, which is provided with ring carbon atoms and at least one, preferably 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In one embodiment, the heteroaryl group has 5-14 ring atoms ("5-14 heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom when valence permits. The heteroaryl bicyclic ring system can contain one or more heteroatoms in one or both rings. In bicyclic heteroaryl groups, one of the rings does not contain heteroatoms (e.g., indolyl, quinolyl, etc.), and the point of attachment can be on either ring, i.e., the ring carrying heteroatoms (e.g., 2-indolyl) or the ring not containing heteroatoms (e.g., 5-indolyl). As used herein, the term "heteroarylene" used alone or as part of another group refers to a divalent group derived from a heteroaryl group as defined herein. Unless otherwise specified or otherwise contrary to the 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 indicated, a heteroaryl group is optionally substituted.

[0390] 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, pyridyl. 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, aza Azepinyl, oxa Oxepinyl and thio Thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzophenylthio, isobenzophenylthio, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0391] "Heteroaralkyl" used alone or as part of another group refers to an alkyl group substituted with one or more heteroaryl groups, preferably substituted with one heteroaryl group. Unless otherwise indicated, the heteroaralkyl group is optionally substituted. When heteroaralkyl is referred to as being optionally substituted, the alkyl portion or the heteroaryl portion of the heteroaralkyl may be optionally substituted.

[0392] As used herein and unless otherwise indicated, the term "amino" refers to -N(R # )(R # ), where each R # may independently be, but are not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is as defined above. # )(R # ) group has two R # When , it can be combined with a 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 are heteroatoms independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. The term "amino" also includes N-oxides (-N + (R # )(R # ) - ). In certain embodiments, each R # Or by -N(R # )(R # ) may independently be unsubstituted or substituted with one or more substituents.

[0393] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic radical, optionally substituted heterocyclic radical, optionally substituted aryl and optionally substituted heteroaryl groups refer to corresponding groups that are unsubstituted or substituted. Typically, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present on a group (such as a carbon or nitrogen atom) is replaced by an allowed substituent (e.g., a substituent that produces a stable compound when substituted, such as a compound that does not spontaneously undergo conversion (e.g., by rearrangement, cyclization, elimination or other reactions)). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent may be the same or different at each position. Typically, when substituted, the optionally substituted group herein may be substituted by 1-5 substituents. Substituent can be carbon atom substituent, nitrogen atom substituent, oxygen atom substituent or sulphur atom substituent, if applicable, each of them can be optionally isotopically labeled, for example deuterated. Two of the optional substituent can be connected to form a ring structure, for example optionally substituted cycloalkyl, heterocyclic radical, aryl or heteroaryl ring. Replacement can occur on any available carbon, oxygen or nitrogen-atoms, and can form a spirocycle. Usually, replacement herein will not result in OO, ON, SS, SN (except SO2-N key), heteroatom-halogen or-C (O)-S key or three or more continuous heteroatoms, except O-SO2-O, O-SO2-N and N-SO2-N, except if in stable aromatic system, some such keys or connections can be allowed.

[0394] In a broad sense, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For appropriate organic compounds, the permissible substituents may be one or more and may be the same or different. For purposes of this disclosure, heteroatoms (such as nitrogen) may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that will satisfy the valence of the heteroatoms. Substituents may include any of the substituents described herein, for example, halogen, hydroxy, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, cycloalkoxy, phosphoryl, phosphate, phosphonate, phosphite, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl or heteroaryl, each of which may be substituted, if applicable.

[0395] Exemplary substituents include, but are not limited to, 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, —NO2, —CN, —SF5, —C(O)OH, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-alkylene-aryl, —S(O)-alkyl, —S(O)2-alkyl, —S(O)-aryl, —S(O)2-aryl, —S(O)-heteroaryl, —S(O)2-heteroaryl, —S-alkyl Y1 and Y2 are the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(═N—CN)—NH2, —C(═NH)—NH2, —C(═NH)—NH(alkyl), —N(Y1)(Y2), -alkylene-N(Y1)(Y2), —C(O)N(Y1)(Y2) and —S(O)2N(Y1)(Y2), wherein Y1 and Y2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.

[0396] Some examples of suitable substituents include, but are not limited to, (C1-C8)alkyl groups, (C2-C8)alkenyl groups, (C2-C8)alkynyl groups, (C3-C 10) cycloalkyl group, halogen (F, Cl, Br or I), halogenated (C1-C8) alkyl group (such as but not limited to -CF3), -O-(C1-C8) alkyl group, -OH, -S-(C1-C8) alkyl group, -SH, -NH(C1-C8) alkyl group, -N((C1-C8) alkyl)2 group, -NH2, -C(O)NH2, -C(O)NH(C1-C8) alkyl group, -C(O)N((C1-C8) alkyl)2, -NHC(O)H, -NHC(O)(C1-C8) alkyl group, -NHC(O)(C3-C8) cycloalkyl group, -N((C1-C8) alkyl)C(O)H, -N((C1-C8) alkyl) )C(O)(C1-C8)alkyl group, —NHC(O)NH2, —NHC(O)NH(C1-C8)alkyl group, —N((C1-C8)alkyl)C(O)NH2 group, —NHC(O)N((C1-C8)alkyl)2 group, —N((C1-C8)alkyl)C(O)N((C1-C8)alkyl)2 group, —N((C1-C8)alkyl)C(O)NH((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(C1-C8)alkyl group, —O-halogenated (C1-C8)alkyl group (for example, but not limited to —OCF3), —S(O)2-halogenated (C1-C8)alkyl group alkyl group (for example, but not limited to -S(O)2CF3), -S-halogenated (C1-C8)alkyl group (for example, but not limited to -SCF3), -(C1-C6)heterocycle (for example, but not limited to pyrrolidine, tetrahydrofuran, pyran or morpholine), -(C1-C6)heteroaryl (for example, but not limited to tetrazole, imidazole, furan, pyrazine or pyrazole), -phenyl, -NHC(O)O-(C1-C6)alkyl group, -N((C1-C6)alkyl)C(O)O-(C1-C6)alkyl group, -C(═NH)-(C1-C6)alkyl group, -C(═NOH)-(C1-C6)alkyl group, or -C(═N-O-(C1-C6)alkyl)-(C1-C6)alkyl group.

[0397] Exemplary carbon atom substituents include, but are not limited to, deuterium, halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3–10 Carbocyclic group, C 6–10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, etc. For example, exemplary carbon atom substituents may include F, Cl, -CN, -SO2H, -SO3H, -OH, -OC 1–6 Alkyl, –NH2, –N(C 1–6 Alkyl)2, –NH(C 1–6 Alkyl), –SH, –SC 1–6 Alkyl, –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 1–6 Alkyl)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 Carbocyclic group, C 6–10 Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal substituents may be linked to form =0.

[0398] The nitrogen atoms may be substituted or unsubstituted as valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, 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 Carbocyclic group, 3-14 membered heterocyclic group, C 6–14 In some embodiments, the substituents present on the nitrogen atom are alkyl, alkyl, alkylene, alkynyl, carbocyclyl, heterocyclyl, aryl, and 5-14 membered heteroaryl, or two substituent groups attached to the nitrogen atom are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be further substituted as defined herein. In certain embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also known as amino protecting groups). Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which are incorporated herein by reference. Exemplary nitrogen protecting groups include, but are not limited to, those that form carbamates, such as a benzyloxycarbonyl (Cbz) group, a p-methoxybenzylcarbonyl (Moz or MeOZ) group, a tert-butoxycarbonyl (BOC) group, Troc, a 9-fluorenylmethoxycarbonyl (Fmoc) group, and the like, those that form amides, such as acetyl, benzoyl, and the like, those that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, and the like, those that form sulfonamides, such as tosyl, nitrobenzenesulfonyl, and the like, and others such as p-methoxyphenyl.

[0399] Exemplary oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 Alkenyl, C 2–10 Alkynyl, C 3–10 Carbocyclic group, 3-14 membered heterocyclic group, C 6–14alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups 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 hydroxy protecting group). Oxygen protecting groups are well known in the art and include those nitrogen protecting groups described in detail in Protective Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those that form alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), and the like, those that form silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), and the like, those that form acetals or ketals, such as tetrahydropyranyl (THP), those that form esters, such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, and the like, those that form carbonates or sulfonates, such as methanesulfonate (mesylate), benzylsulfonate, tosylate (Ts), and the like.

[0400] Unless expressly stated to the contrary, combinations of substituents and / or variables are permissible only if such combinations are chemically permitted and result in stable compounds. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain or can be left substantially 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).

[0401] In some embodiments, the "optionally substituted" alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocycle, carbocyclylene, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclyl, or heterocyclylene herein may each independently be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of deuterium, F, Cl, -OH, protected hydroxy, oxo (if applicable), NH2, protected amino, NH(C 1-4 Alkyl) or its protected derivatives, N(C 1-4 Alkyl ((C 1-4 Alkyl), C 1-4 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, 3-7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyloxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from deuterium, F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl (e.g., CF3), C 1-4 Alkoxy and fluorine substituted C 1-4 In some embodiments, the "optionally substituted" aryl, arylene, heteroaryl or heteroarylene groups herein may each independently be unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of deuterium, F, Cl, -OH, -CN, NH2, 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 3-6 cycloalkyloxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, 3-7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from deuterium, F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy and fluorine substituted C 1-4 Alkoxy.

[0402] "Halo" or "halogen" refers to fluorine (fluorine or fluoro, -F), chlorine (chlorine or chloro, -Cl), bromine (bromine or bromo, -Br) or iodine (iodine or iodo, -I).

[0403] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts.

[0404] Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic ... Sugar acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric 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, undecylenic acid, etc.

[0405] Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts prepared by adding an inorganic base or an 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, aluminum salts, and the like. 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, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenethylbenzylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. In one embodiment, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0406] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from tautomerism. The exact ratio of tautomers depends on several factors, including, for example, temperature, solvent, and pH. Tautomerism is known to those skilled in the art. Exemplary tautomerisms include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different) enamine tautomerism.

[0407] As used herein, the term "subject" (alternatively referred to herein as "patient") refers to an animal, preferably a mammal, and most preferably a human, who has been the object of treatment, observation, or experiment.

[0408] As used herein, and unless otherwise indicated, the terms "treat," "treating," "treatment," and the like refer to the elimination, reduction, or amelioration of a disease or condition and / or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require complete elimination of the disease, condition, or symptoms associated therewith. The term "treating" and synonyms contemplate administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0409] As used herein, and unless otherwise indicated, the terms "prevent," "preventing," "prevention," and the like refer to reducing the probability of the onset of a disease or condition, recurrence of a disease or condition, or recurrence of a previously controlled disease or condition in a subject who does not have the disease or condition, but is at risk or susceptible to developing or redeveloping a disease or condition, or who is at risk or susceptible to a recurrence of a disease or condition.

[0410] The term "effective amount" refers to an amount of a compound or combination of compounds as described herein sufficient to achieve the intended application (including but not limited to preventing or treating a disease). The therapeutically effective amount can be changed according to the following: the intended administration (in vitro or in vivo), or the subject and the disease condition being treated (e.g., the subject's weight, age and gender), the severity of the disease condition, the mode of administration, etc., which can be easily determined by a person of ordinary skill in the art. The term is also applicable to doses that will induce a specific response in target cells and / or tissues. The specific dose will be changed according to the following: the specific compound selected, the subsequent dosing regimen (whether or not the compound is combined with other compounds), the time of administration, the tissue to be administered, and the physical delivery system carrying the compound.

[0411] As used herein, the singular forms "a," "an," and "the" include plural referents unless expressly specified or clear from the context.

[0412] As used herein, the terms "comprising" and "including" are used interchangeably. The terms "comprising" and "including" should be interpreted as specifying the presence of the claimed features or components as mentioned, but not excluding the presence or addition of one or more features or components or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples covered by the term "consisting of". Therefore, the term "consisting of" can be used instead of the terms "comprising" and "including" to provide more specific embodiments.

[0413] 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". An exception to this definition will only occur if the combination of elements, functions, steps or actions is inherently mutually exclusive to some extent.

[0414] The term "and / or" as used herein, as in phrases such as "A and / or B," is intended to include A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or," as used 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).

[0415] It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure will be given greater weight.

[0416] As used herein and unless otherwise indicated, the term "about" or "approximately" means an acceptable error for a particular value determined by one of ordinary skill in the art, which will depend 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.

[0417] The titles and subtitles are used for convenience and / or formal compliance only, do not limit the subject technology, and are not related to the interpretation of the description of the subject technology. In various embodiments, the features described under one title or one subtitle of the subject disclosure can be combined with the features described under other titles or subtitles. In addition, all features under a single title or a single subtitle are not necessarily used together in an embodiment.

[0418] Examples

[0419] The various starting materials, intermediates and compounds of the embodiments herein can be separated and purified using conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation and chromatography, where appropriate. The characterization of these compounds can be carried out using conventional methods, such as by melting point, mass spectrum, nuclear magnetic resonance and various other spectral analyses. The abbreviations used in the examples section should be understood to have their common meanings in the art, unless otherwise specifically stated or clearly contrary to the context. The examples are illustrative only and do not limit the claimed invention in any way.

[0420] Exemplary embodiments of the steps for performing 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 appreciated by those of ordinary skill in the art, prior to the chiral separation step, for example by supercritical fluid chromatography (SFC), the compounds described in the Examples section exist as racemic and / or stereoisomeric mixtures, with boldface rather than wedge-shaped bonds used in the chemical structure diagrams to indicate relative stereochemistry. It should be understood that the enantiomeric excess ("ee") and / or diastereomeric excess ("de") reported for these examples represent only exemplary procedures herein, and are not restrictive; those skilled in the art will appreciate that, in view of this disclosure, such enantiomers with different ee and / or de, for example, higher ee, and / or higher de, can be obtained.

[0421] In some illustrative examples, the synthesis of deuterated compounds is shown. Where applicable, it is understood that the corresponding non-deuterated (ie, having natural abundance) compounds are prepared by the same methods except that the corresponding non-deuterated starting materials or intermediates are used.

[0422] Synthesis of boronate intermediates

[0423] 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]

[0424] Naphthyridine (Int-1)

[0425] As starting material, S-1.1 was obtained according to the procedure of Exhibit 24 in the Examples section, and it was subjected to substitution, hydrolysis, fluorination to provide S-1.4. Int-1 was then synthesized by reduction and borylation from S-1.4.

[0426]

[0427] 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)

[0428] Int-2 was synthesized starting from S-2.1 according to the following synthetic route. First, S-2.9 was obtained by a procedure similar to Exhibit 24 in the Examples section. Then Int-2 was obtained from S-2.9 by reduction and borylation by a procedure similar to Exhibit 27 in the Examples section.

[0429]

[0430] 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)

[0431] Int-3 was synthesized starting from S-1.3 according to the following synthetic route.

[0432]

[0433] 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'-

[0434] Cyclopropane](Int-4)

[0435] Int-4 was synthesized starting from S-2.9 according to the following synthetic route.

[0436]

[0437] 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

[0438] -3,1'-cyclopropane](Int-5)

[0439] Int-5 was synthesized starting from S-4.2 according to the following synthetic route.

[0440]

[0441] Example 1. (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran

[0442] Synthesis of -3-ol (1)

[0443]

[0444] At 0 ° C, lithium aluminum hydride (0.32 g, 8.55 mmol) was added to a solution of 2-amino-5-bromo-3-fluorobenzoic acid (1.1, 1.00 g, 4.27 mmol) in tetrahydrofuran (20 mL) in batches, 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 obtain (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) δ7.16 (dd, J = 10.3, 2.2Hz, 1H), 7.07-7.04 (m, 1H), 4.70 (s, 2H), 4.28 (brs, 2H).

[0445] 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) δ9.87 (d, J = 2.0 Hz, 1H), 7.51-7.45 (m, 1H), 7.33 (dd, J = 10.6, 2.2 Hz, 1H), 6.20 (brs, 2H).

[0446] A mixture of 2-amino-5-bromo-3-fluorobenzene-1-carbaldehyde (1.3, 470 mg, 2.16 mmol), ethyl prop-2-ynoate (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] + . 1H NMR (400MHz, CDCl3) δ9.52 (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).

[0447] Under nitrogen atmosphere, at 0 ° C, methylmagnesium bromide (1.68 mL, 5.03 mmol, 3M in 2-methyltetrahydrofuran) was added dropwise to a solution of ethyl 6-bromo-8-fluoroquinoline-3-carboxylate (1.4, 300 mg, 1.06 mmol) in tetrahydrofuran (10 mL), 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 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 obtain 2-(6-bromo-8-fluoroquinoline-3-yl)propane-2-ol (1.5, 270 mg, 94%) as a yellow solid. LC-MS (ESI): m / z 284.0 [M+H] + .

[0448] 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-dioxaborolan (215 mg, 0.84 mmol), potassium acetate (207 mg, 2.11 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (57.6 mg, 0.07 mmol) in dioxane (4 mL) was stirred at 90° C. for 4 hours under a nitrogen atmosphere. 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] + .

[0449] 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] + .

[0450] 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] + . 1 H NMR (400MHz, DMSO-d6) δ9.21 (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).

[0451] Example 2. Synthesis of 4-(8-fluoro-3-(2-hydroxypropane-2-yl)quinolin-6-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carbonitrile (2)

[0452]

[0453] 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] + .

[0454] 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] + . 1H NMR (400MHz, DMSO-d6) δ9.24(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),3.43-3.4 0(m,1H),3.16-3.03(m,1H),2.02-1.87(m,1H),1.61(s,6H),1.60-1.53(m,1H).

[0455] Example 3. (3S,4R)-4-((5-chloro-4-(4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0456] (3) Synthesis

[0457]

[0458] Under nitrogen atmosphere, at 0 ° C, methylmagnesium bromide (4mL, 3M in diethyl ether) was added dropwise to a solution of 6-bromoquinoline-4-formic acid methyl ester (3.1, 800mg, 3.00mmol) in anhydrous tetrahydrofuran (15mL), and the mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. At 0 ° C, the reaction mixture was quenched with saturated NH4Cl (20mL) solution and extracted with ethyl acetate (15mL×2). The combined organic layer was washed with brine (10mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2-(6-bromoquinoline-4-yl)propane-2-ol (3.2, 564mg, 71%). LC-MS (ESI): m / z 266.0[M+H] + .

[0459] 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-dioxaborolane-2-yl)-1,3,2-dioxaborolane (209 mg, 0.82 mmol) in dioxane (4 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.0 mg, 0.04 mmol) and potassium acetate (255 mg, 2.60 mmol), and the mixture was stirred at 90° C. for 2 hours under a nitrogen atmosphere. 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 obtain 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] + .

[0460] 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) was added tetrakis(triphenylphosphine)palladium(0) (48.0 mg, 0.04 mmol) and potassium carbonate (114 mg, 0.83 mmol), and the mixture was stirred at 90 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (20 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-(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] + .

[0461] 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) was added N,N-diisopropylethylamine (125 uL, 0.75 mmol) 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-hydroxypropane-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] + . 1 H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 8.89 (d, J = 4.6Hz, 1H), 8.45 (s, 1H), 8.13 (d, J=8.6Hz,1H),8.09-8.00(m,1H),7.59(d,J=4.7Hz,1H),7.49(d,J=6.5Hz,1H),5.6 0(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).

[0462] 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)

[0463]

[0464] 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 hours. The reaction mixture was cooled to room temperature, adjusted to pH 5-6 with 10% HCl, and then filtered. The filter cake was washed with warm 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] + .

[0465] 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 sulfuryl chloride (963 uL, 13.2 mmol) dropwise at 0°C, and the mixture was then stirred at 60°C for 5 hours. 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] + .

[0466] Under nitrogen atmosphere, at 0°C, to a solution of 6-bromo-2-methylquinoline-4-carboxylic acid methyl ester (4.3, 1.90 g, crude product) in anhydrous tetrahydrofuran (20 mL) was added methylmagnesium bromide (8.84 mL, 26.5 mmol, 3 M in diethyl ether), and the mixture was stirred at room temperature overnight. At 0°C, the reaction mixture was quenched with saturated NH4Cl (20 mL) solution 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 obtain 2-(6-bromo-2-methylquinoline-4-yl)propane-2-ol (4.4, 1.07 g). LC-MS (ESI): m / z 280.0[M+H] + .

[0467] To a mixture of 2-(6-bromo-2-methylquinoline-4-yl)propane-2-ol (4.4, 600 mg, 2.15 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolane-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 for 2 hours under a nitrogen atmosphere. 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] + .

[0468] To a mixture of 2-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-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 for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (15 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-(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] + .

[0469] 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-chloroperoxybenzoic 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] + .

[0470] 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 and 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) δ9.23 (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).

[0471] Example 5. (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro

[0472] -Synthesis of 2H-pyran-3-ol (5)

[0473]

[0474] A mixture of 2-amino-5-bromo-3-fluorobenzene-1-carbaldehyde (1.3, 400 mg, 1.83 mmol), ethyl but-2-ynoate (617 mg, 5.51 mmol) and L-proline (127 mg, 1.10 mmol) in ethanol (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) δ8.67 (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).

[0475] Under nitrogen atmosphere, at 0 ° C, methylmagnesium bromide (3.20 mL, 9.61 mmol, 3M in 2-methyltetrahydrofuran) was added dropwise to a solution of ethyl 6-bromo-8-fluoro-2-methylquinoline-3-carboxylate (5.1, 600 mg, 1.92 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at 25 ° C for 4 hours under nitrogen atmosphere. The reaction mixture was extracted with saturated ammonium chloride solution (5 mL), diluted with water (20 mL) and extracted with ethyl acetate (15 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 obtain 2-(6-bromo-8-fluoro-2-methylquinolin-3-yl)propane-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) δ8.19 (s, 1H), 7.78 (s, 1H), 7.51 (dd, J = 9.8, 2.0Hz, 1H), 3.04 (s, 3H), 1.81 (s, 6H).

[0476] 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-dioxaborolan (347 mg, 1.37 mmol), potassium acetate (336 mg, 3.42 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (93.0 mg, 0.11 mmol) in dioxane (10 mL) was stirred at 90° C. for 1 hour under a nitrogen atmosphere. 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 obtain 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] + . 1H NMR (400MHz, CDCl3) δ8.27 (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).

[0477] 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. for 2 hours under a nitrogen atmosphere. 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) δ8.75 (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).

[0478] 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] + . 1HNMR (400MHz, DMSO-d6) δ8.50(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).

[0479] Example 6. (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro

[0480] -Synthesis of 2H-pyran-3-ol (6)

[0481]

[0482] Under nitrogen atmosphere, at 0 ° C, methylmagnesium bromide (2.38 mL, 7.14 mmol, 3M in 2-methyltetrahydrofuran) was added dropwise to a solution of ethyl 6-bromoquinoline-3-carboxylate (6.1, 400 mg, 1.43 mmol) in tetrahydrofuran (10 mL), 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 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 obtain 2- (6-bromoquinolin-3-yl) propane-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) δ9.08 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.79 (dd, J = 9.0, 2.2 Hz, 1H), 1.74 (s, 6H).

[0483] 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-dioxaborolan (412 mg, 1.62 mmol), potassium acetate (398 mg, 4.06 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (111 mg, 0.13 mmol) in dioxane (10 mL) was stirred at 90° C. for 12 hours under a nitrogen atmosphere. 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] + .

[0484] 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. for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to give 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] + .

[0485] 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) δ9.16(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).

[0486] Example 7. (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro

[0487] -Synthesis of 2H-pyran-3-ol (7)

[0488]

[0489] 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) δ7.40-7.31 (m, 2H), 4.57 (brs, 2H).

[0490] Under nitrogen atmosphere, methylmagnesium bromide (3.10 mL, 9.30 mmol, 3M in 2-methyltetrahydrofuran) was added dropwise to a solution of 2-amino-5-bromo-3-fluorobenzene-1-carbonitrile (7.2, 400 mg, 1.86 mmol) in tetrahydrofuran (5 mL) at 0 ° C, and the mixture was stirred at 25 ° C for 12 hours under nitrogen atmosphere. The reaction mixture was extracted with saturated ammonium chloride solution (5 mL), diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). 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 obtain 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) δ7.78 (s, 1H), 7.57 (dd, J = 11.0, 2.2Hz, 1H), 7.21 (s, 2H), 2.57 (s, 3H).

[0491] A mixture of 1-(2-amino-5-bromo-3-fluorophenyl)ethan-1-one (7.3, 300 mg, 1.29 mmol), ethyl prop-2-ynoate (1.02 g, 10.34 mmol) and copper 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] + .

[0492] Under nitrogen atmosphere, at 0 ° C, methylmagnesium bromide (1.44 mL, 4.33 mmol, 3M in 2-methyltetrahydrofuran) was added dropwise to a solution of 6-bromo-8-fluoro-4-methylquinoline-3-carboxylic acid ethyl ester (7.4, 300 mg, 1.07 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at 25 ° C for 1 hour under nitrogen atmosphere. The reaction mixture was extracted with saturated ammonium chloride solution (5 mL), diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). 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 obtain 2-(6-bromo-8-fluoro-4-methylquinolin-3-yl)propane-2-ol (7.5, 70 mg, 27%) as a yellow oil. LC-MS (ESI): m / z 298.0 [M+H] + .

[0493] 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-dioxaborolan (71.6 mg, 0.28 mmol), potassium acetate (69 mg, 0.704 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (19.2 mg, 0.02 mmol) in dioxane (10 mL) was stirred at 90° C. for 1 hour under a nitrogen atmosphere. 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 obtain 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] + .

[0494] 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. for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to give 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] + .

[0495] 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 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)-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 HNMR(400MHz,DMSO-d6)δ9.14(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).

[0496] 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)

[0497]

[0498] At 0 ° C, to a mixture of 4-oxopiperidine-1,3-dicarboxylic acid 1-(tert-butyl) 3-ethyl ester (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 dropwise a solution of trifluoromethanesulfonic anhydride (18.7 g, 66.4 mmol, 11 mL) in dichloromethane (50 mL), and the resulting mixture was stirred at 0 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with a 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] + .

[0499] 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-dioxaborolan (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), and the mixture was stirred at 110 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (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 obtain 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1,3(2H)-dicarboxylic acid 1-(tert-butyl) 3-ethyl ester (8.3, 11.0 g, 58%) as a yellow oil. LC-MS (ESI): m / z 382.2 [M+H] + .

[0500] To a solution of 4-bromo-2-fluoro-6-iodoaniline (9.11 g, 28.9 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-pyridine-1,3(2H)-dicarboxylic acid 1-(tert-butyl) 3-ethyl ester (8.3, 11.0 g, 28.9 mmol) in dioxane (150 mL) and water (15 mL) was added sodium carbonate (9.17 g, 86.6 mmol) and Pd(dppf)Cl2 (1.06 g, 1.44 mmol), and the resulting mixture was stirred at 50 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with ethanol (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).

[0501] Phosphorus oxychloride (8.68 g, 56.6 mmol) and N,N-diisopropylethylamine (7.32 g, 56.6 mmol) were added 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), 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 ground with saturated sodium bicarbonate solution (50 mL). The filter cake was dried in vacuo, diluted with phosphorus oxychloride (20 mL), and then stirred at 100 ° C for another 2 hours. The mixture was concentrated under reduced pressure and ground 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 ground 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] + .

[0502] Zinc powder (2.07 g, 31.7 mmol) was added in batches 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), 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 layer was 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] + .

[0503] 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 obtain tert-butyl 9-bromo-7-fluoro-1,4-dihydrobenzo[c][2,7]naphthyridine-3(2H)-carboxylate (8.7, 0.50 g) as a light yellow solid. LC-MS(ESI):m / z 381.1[M+H] + .

[0504] 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (366 mg, 1.44 mmol), potassium acetate (386 mg, 3.93 mmol) and Pd(dppf)Cl2 (96.0 mg, 131 umol) were added 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), and the mixture was stirred at 90 ° C. for 1 hour under a nitrogen atmosphere. 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] + .

[0505] 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) was added Pd(PPh3)4 (54.0 mg, 0.05 mmol) and potassium carbonate (64.5 mg, 0.47 mmol), and the reaction was stirred at 90 ° C for 4 hours under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 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] + .

[0506] 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 layers were washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 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] + .

[0507] 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) δ8.76(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),3.83-3.7 9(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).

[0508] 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)

[0509]

[0510] At 0 ° C, to 3-oxopiperidin-1,4-dicarboxylic acid 1- (tert-butyl) 4-ethyl ester (9.1, 25.0g, 92.2mmol) and N, N-diisopropylethylamine (35.7g, 276mmol, 48.2mL) in dichloromethane (600mL) in a mixture of trifluoromethanesulfonic anhydride (31.2g, 111mmol, 18.2mL) in dichloromethane (70mL) was added dropwise. The resulting mixture was stirred at 0 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (500mL) and extracted with dichloromethane (200mLx 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)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] + .

[0511] To a solution of 1-(tert-butyl)4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,4(2H)-dicarboxylate (9.2, 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-dioxaborolan (24.2 g, 95.5 mmol), potassium acetate (25.6 g, 260 mmol) and Pd(dppf)Cl 2· CHCl (7.09 g, 8.68 mmol), and the mixture was stirred at 110 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (700 mL) and extracted with ethyl acetate (300 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 5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1,4(2H)-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (9.3, 30.0 g, 77%) as a yellow oil. LC-MS (ESI): m / z 282.2 [M-100+H] + .

[0512] Under nitrogen atmosphere, sodium carbonate (8.34 g, 78.7 mmol) and Pd (dppf) Cl2 (960 mg, 1.31 mmol) were added to a mixture of 4-bromo-2-fluoro-6-iodoaniline (8.29 g, 26.2 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1,4 (2H)-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (9.3, 10.0 g, 26.2 mmol) in dioxane (100 mL) and water (10 mL), and the resulting mixture was stirred at 50 ° C. for 3 hours under nitrogen atmosphere. 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 ethanol (50 mL) at 25 ° C for 1 hour and then filtered. 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] + .

[0513] 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, 4M 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]naphthyridine-5(1H)-one (9.5, 5.00 g, crude) as a yellow solid. LC-MS (ESI): m / z 297.0 [M+H] + .

[0514] A mixture of 9-bromo-7-fluoro-2,3,4,6-tetrahydrobenzo[c][2,6]naphthyridine-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 ground with methyl tert-butyl ether (100 mL) at 25 ° C for 30 minutes. The resulting mixture was filtered and the filter cake was dried under vacuum 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 layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 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] + .

[0515] 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 10M sodium hydroxide solution. The resulting mixture was filtered and the filtrate was extracted with dichloromethane (50 mL×3). The combined organic layer was 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] + .

[0516] 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) was 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 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 obtain 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]+ .

[0517] 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (322 mg, 1.27 mmol), potassium acetate (340 mg, 3.46 mmol) and Pd(dppf)Cl2 (84.5 mg, 115 umol) were added 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). The resulting mixture was stirred at 90 ° C for 2 hours under a nitrogen atmosphere. 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]+.

[0518] 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 uL, 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 for 4 hours under a nitrogen atmosphere. 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 obtain 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] + .

[0519] 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 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-(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), which was provided as a white solid. LC-MS (ESI): m / z 530.2 [M+H] + .

[0520] 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, 4M 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 then 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][2,6]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] + . 1H NMR (400MHz, DMSO-d6) δ8.75(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).

[0521] Example 10. (3S,4R)-4-((5-chloro-4-(2-methyl-3H-imidazo[4,5-c]quinolin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran

[0522] Synthesis of -3-ol (10)

[0523]

[0524] 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)Cl2 (387 mg, 529 umol) in dioxane (10 mL) and water (1 mL) was stirred at 90 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain 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] + .

[0525] 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) was 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 hours. 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 obtain 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] + .

[0526] 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'-di(1,3,2-dioxaborolane) (958 mg, 3.77 mmol), tris(dibenzylideneacetone)dipalladium (138 mg, 151 umol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (124 mg, 302 umol) 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)δ9.16(s,1H),8.96(s,1H),8.27(s,2H),8.00(s,2H),7.2 0(d,J=8.4Hz,2H),6.91(d,J=8.4Hz,2H),5.62(s,2H),3.70(s,3H),2.69(s,3H).

[0527] 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) was added Pd(PPh3)4 (54 mg, 0.05 mmol) and potassium carbonate (64.0 mg, 0.46 mmol), and the mixture was stirred at 90°C for 4 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 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 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] + .

[0528] 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 hour. 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] + .

[0529] 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), adjusted to pH 8 with saturated sodium carbonate solution, and then extracted with dichloromethane (10 mL×3). The combined organic layers were 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) δ9.13(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).

[0530] Example 11. (3S,4R)-4-((5-chloro-4-(1-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran

[0531] Synthesis of -3-ol (11)

[0532]

[0533] At 0 ° C, lithium aluminum hydride (1.28 g, 33.7 mmol) was added to a mixture of 4-bromo-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (11.1, 7.85 g, 33.7 mmol) in tetrahydrofuran (80 mL) in batches, and then the mixture was stirred for 3 hours at 0 ° C under a nitrogen atmosphere. At 0 ° C, the reaction mixture was slowly quenched with a saturated sodium chloride solution (6 mL) 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 obtain 4-bromo-5-methyl-1H-pyrazole-3-carboxaldehyde (11.2, 1.80 g, 28%) as a white solid. LC-MS (ESI): m / z 189.1 [M+H] + .

[0534] To a mixture of 4-bromo-5-methyl-1H-pyrazole-3-carboxaldehyde (11.2, 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-dichloropalladium(II) dichloromethane complex (389 mg, 476 umol), and the resulting mixture was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (50 mL×3). The combined organic layer was 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] + .

[0535] 3,4-dihydro-2H-pyran (352 mg, 4.18 mmol) and p-toluenesulfonic acid monohydrate (79.5 mg, 418 umol) were added 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), 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 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 obtain 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] + .

[0536] 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'-di(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)phosphine (161 mg, 338 umol) in tetrahydrofuran (10 mL) was added palladium(II) acetate (38.0 mg, 169 umol), and the resulting mixture was stirred at 70° C. for 2 hours under a nitrogen atmosphere. 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] + .

[0537] 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) was added tetrakis(triphenylphosphine)palladium(0) (59.0 mg, 0.05 mmol) and potassium carbonate (107 mg, 0.77 mmol), and the resulting mixture was stirred at 90 ° C for 4 hours under a nitrogen atmosphere. 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 obtain 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] + .

[0538] 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] + .

[0539] 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, 4M 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), adjusted to pH 8 with saturated sodium carbonate solution, and then extracted with dichloromethane (10 mL×3). The combined organic layers were 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) δ13.72(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).

[0540] Example 12. (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyridine-2-yl

[0541] Synthesis of (4-(2-amino)tetrahydro-2H-pyran-3-ol (12)

[0542]

[0543] 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(PPh3)4 (31.9 mg, 0.03 mmol) and potassium carbonate (76.3 mg, 0.55 mmol), and the resulting mixture was stirred at 110°C for 3 hours under a nitrogen atmosphere. 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] + .

[0544] 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) was 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 layers were 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] + . 1H NMR(400MHz, DMSO-d6)δ8.06(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).

[0545] Example 13. (3S,4R)-4-((5-chloro-4-(1-methyl-3,4-dihydrobenzopyrano[3,4-c]pyrazol-8-yl)pyrimidin-2-yl)amino)tetrahydro

[0546] -Synthesis of 2H-pyran-3-ol (13)

[0547]

[0548] 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) was added 3,4-dihydro-2H-pyran (4.00 mL, 42.9 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 obtain 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] + .

[0549] Under nitrogen atmosphere, lithium borohydride (1.15 g, 53.0 mmol) was added 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) at 0°C, and the mixture was stirred at 25°C for 14 hours under nitrogen atmosphere. The reaction mixture was poured into ice water (200 mL) and 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 product) as a white solid. LC-MS(ESI):m / z 275.2[M+H] + .

[0550] 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) was added XPhos Pd G3 (1.11 g, 1.31 mmol), and the resulting mixture was stirred at 90 ° C for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (200 mL), and 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. 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] + .

[0551] Palladium (1.00 g, 10% on carbon) was added 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). The resulting mixture was degassed and backfilled with hydrogen three times, and then stirred at room temperature for 15 minutes under a hydrogen atmosphere (1 atm). 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] + .

[0552] At 0°C, 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), and the mixture was stirred at 25°C for 2 hours under a nitrogen atmosphere. 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 obtain 8-chloro-1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3,4-dihydrobenzopyrano[3,4-c]pyrazole (13.6, 520 mg) as a yellow solid. LC-MS (ESI): 305.2 [M+H] + .

[0553] To a mixture of 8-chloro-1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3,4-dihydrobenzopyrano[3,4-c]pyrazole (13.6, 450 mg, 1.48 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(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 Pd2(dba)3 (136 mg, 0.15 mmol), and the resulting mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1-methyl-3-(tetrahydro-2H-pyran-2-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzopyrano[3,4-c]pyrazole (13.7, 366 mg, 26%) as a yellow solid. LC-MS (ESI): 397.3 [M+H] + .

[0554] 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-dihydrobenzopyrano[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 obtain 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] + .

[0555] 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 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain (3S,4R)-4-((5-chloro-4-(1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3,4-dihydrobenzopyrano[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] + .

[0556] To a solution of (3S,4R)-4-((5-chloro-4-(1-methyl-3-(tetrahydro-2H-pyran-2-yl)-3,4-dihydrobenzopyrano[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) 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 then 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-dihydrobenzopyrano[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] + . 1H NMR (400MHz, DMSO-d6) δ12.75(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).

[0557] 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)

[0558]

[0559] At 0 ° C, sulfuric acid (1.5 mL, 28.2 mmol) was added dropwise 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), and the mixture was stirred at 25 ° C for 12 hours. The reaction mixture was poured into water (20 mL), adjusted to pH 9 with 1M aqueous sodium hydroxide solution, and then extracted 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 obtain 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] + .

[0560] 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-dioxaborolan (628 mg, 2.47 mmol), potassium acetate (607 mg, 6.18 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (169 mg, 0.20 mmol) in dioxane (5 mL) was stirred at 90° C. for 1 hour under a nitrogen atmosphere. 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 obtain 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] + .

[0561] 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. for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to give 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] + .

[0562] 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 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 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] + .

[0563] 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 obtain 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] + . 1H NMR (500MHz, DMSO-d6) δ9.29(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,1H),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).

[0564] 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)

[0565]

[0566] 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 obtain 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] + .

[0567] At 0 ° C, sodium borohydride (204 mg, 5.40 mmol) was added 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), 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 layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 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] + .

[0568] A mixture of 1-(6-bromo-8-fluoro-2,4-dimethylquinolin-3-yl)ethan-1-ol (15.3, 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-dioxaborolan (194 mg, 0.76 mmol), potassium acetate (187 mg, 1.91 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (52.2 mg, 0.06 mmol) in dioxane (4.0 mL) was stirred at 90° C. for 1 hour under a nitrogen atmosphere. 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 obtain 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] + .

[0569] 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. for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to give 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] + .

[0570] 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:

[0571] Isomer 1: (15a, 100% ee); retention time: 0.522 min. LC-MS (ESI): m / z 447.2 [M+H] + ; 1HNMR(500MHz,DMSO-d6)δ8.47(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).

[0572] Isomer 2: (15b, 100% ee); retention time: 1.280 min; LC-MS (ESI): m / z 447.2 [M+H] + . 1 HNMR(500MHz,DMSO-d6)δ8.47(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).

[0573] Analytical separation method: Column: CHIRALPAK IH-3, 4.6×50 mm, 3.0 um; A, MTBE (0.1% DEA), and B, MeOH; Gradient: 3.6 min@B 50%; Flow rate: 1.67 mL / min; High pressure: 76 bar; Column temperature: 25° C.

[0574] Preparative separation method: instrument: GILSON-03; column: CHIRALPAK IH-3, 20×250 mm, 5 um; mobile phase: A, MTBE (0.1% DEA), and B, MeOH; gradient: B 50%; flow rate: 20 mL / min; high pressure: 78 bar; column temperature: 25° C.

[0575] Example 16. (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(1-hydroxycyclobutyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl

[0576] Synthesis of alcohol (16)

[0577]

[0578] N-iodosuccinimide (49.8 g, 221 mmol) was added to a solution of 6-bromo-8-fluoroquinoline (16.1, 10.0 g, 44.2 mmol) in acetic acid (80 mL), 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 obtain 6-bromo-8-fluoro-3-iodoquinoline (16.2, 9.00 g, 57%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.12 (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).

[0579] Under nitrogen atmosphere, at -78 ° C, isopropylmagnesium chloride (5.25 mL, 1.30 M in tetrahydrofuran) was added dropwise to a solution of 6-bromo-8-fluoro-3-iodoquinoline (16.2, 2.00 g, 5.68 mmol) in tetrahydrofuran (30 mL). The mixture was stirred at -78 ° C for 1 hour, followed by the addition of a solution of cyclobutanone (597 mg, 8.52 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at -78 ° C for 3 hours, then slowly warmed to 25 ° C and stirred for another 8 hours. The reaction mixture was poured into saturated ammonium chloride (100 mL) and extracted with ethyl acetate (40 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-(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] + .

[0580] 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) were 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] + .

[0581] To a mixture of 1-(8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)quinolin-3-yl)cyclobutane-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 for 2 hours under a nitrogen atmosphere. 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] + .

[0582] 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)δ9.18(d,J=2.2Hz,1H),8.59(t,J=1.9Hz,1H),8.48(s,1H),8.32(s ,1H),7.86(d,J=12.6Hz,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).

[0583] Example 17. (3S,4R)-4-((5-chloro-4-(4-chloro-8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-

[0584] Synthesis of pyran-3-ol (17)

[0585]

[0586] To a solution of 4-bromo-2-fluoroaniline (9.46 g, 49.8 mmol) in toluene (40 mL) was added diethyl 2-(ethoxymethylene)malonate (17.1, 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] + .

[0587] 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 at 100° C. overnight 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] + .

[0588] 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 obtain 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] + .

[0589] At 0 ° C, methylmagnesium bromide (3 mL, 1M in tetrahydrofuran) was added to a solution of 6-bromo-4-chloro-8-fluoroquinoline-3-carboxylic acid ethyl ester (17.4, 190 mg, 0.57 mmol) in tetrahydrofuran (5 mL), 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 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 obtain 2- (6-bromo-4-chloro-8-fluoroquinoline-3-yl) propane-2-ol (17.5, 182 mg, 52%). LC-MS (ESI): m / z 318.0 [M + H] +and 319.9[M+2+H] + .

[0590] 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-dioxaborolan (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. for 4 hours under a nitrogen atmosphere. 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 obtain (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] + .

[0591] To a mixture of (4-chloro-8-fluoro-3-(2-hydroxypropane-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 for 2 hours under a nitrogen atmosphere. 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 obtain 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] + .

[0592] 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] + . 1 H NMR (500MHz, DMSO-d6) δ9.43(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 ),3.88-3.79(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).

[0593] Example 18. (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(5-methyl-1H-imidazol-4-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-

[0594] Synthesis of pyran-3-ol (18)

[0595]

[0596] 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, then 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 obtain 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] + .

[0597] 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. The mixture was stirred at 0°C for 1 hour, followed by the addition of tributyl(chloro)stannane (1.25 mL, 4.64 mmol), 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×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] + .

[0598] 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, 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 obtain 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] + .

[0599] To a mixture of 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 (1.04 g, 4.10 mmol) and potassium acetate (604 mg, 6.15 mmol) in 1,4-dioxane (10 mL) were added 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-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 for 12 hours under a nitrogen atmosphere. 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 obtain 8-fluoro-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazole-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] + .

[0600] 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] + .

[0601] 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 layers were washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give (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] + .

[0602] 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, 4M 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] + . 1 H NMR(500MHz,DMSO-d6)δ12.29(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).

[0603] Example 19. (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)pyrimidine

[0604] Synthesis of tetrahydro-2H-pyran-3-ol (19)

[0605]

[0606] 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) were added sodium carbonate (3.68 g, 34.7 mmol) and (2-(trimethylsilyl)ethyl)carboxylic acid 2,5-dioxopyrrolidin-1-yl ester (5.39 g, 20.8 mmol), 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 obtain (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] + .

[0607] At 0°C, diisopropyl azodicarboxylate (2.92 g, 14.4 mmol, 2.54 mL) was added dropwise to a mixture of (R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid 4-(tert-butyl) 1-(2,2,2-trichloroethyl) ester (19.2, 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), and the resulting mixture was stirred at room temperature for 14 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3). 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 obtain (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] + .

[0608] 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 (R)-tert-butyl 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] + .

[0609] To a solution of (R)-9-bromo-7-fluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (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-dioxaborolan (787 mg, 3.10 mmol), potassium acetate (760 mg, 7.74 mmol) and Pd(dppf)Cl2 (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 layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give (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)-carboxylic acid tert-butyl ester (19.5, 340 mg, 30%) as a yellow solid. LC-MS (ESI): m / z 435.2 [M+H] + .

[0610] 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)-carboxylic acid tert-butyl ester (19.5, 340 mg, 0.78 mmol) and 2,4,5-trichloropyrimidine (1.7, 100 uL, 0.86 mmol) in water (0.5 mL) and dioxane (2 mL) was added Pd(PPh3)4 (135 mg, 0.11 mmol) and potassium carbonate (216 mg, 1.56 mmol). The reaction mixture was stirred at 90 ° C for 15 hours under a nitrogen atmosphere. 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 (R)-tert-butyl 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] + .

[0611] 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)-carboxylic acid tert-butyl ester (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 layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give (R)-tert-butyl 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] + .

[0612] To a solution of (R)-tert-butyl 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 then 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)δ8.34(s,1H),7.38(d,J=8.0Hz,1H),7.16-7.01(m,2H),4.88(brs,1H),4.38 (dd,J=10.8,2.8Hz,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(t d,J=11.8,3.2Hz,1H),2.40(t,J=11.4Hz,1H),1.93(d,J=13.2Hz,1H),1.48(qd,J=11.8,4.5Hz,1H).

[0613] Example 20. Synthesis of (3S,4R)-4-((5-chloro-4-(4-fluoro-8,9,10,11-tetrahydro-7H-8,11-aminocyclohepta[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-aminocyclohepta[c]quinolin-2-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (20b)

[0614]

[0615] At 0 ° C, sodium hydride (3.46 g, 86.4 mmol, 60% suspension in mineral oil) was added to a mixture of diethyl 2-(diethoxyphosphoryl)acetate (20.5 g, 91.5 mmol) in tetrahydrofuran (80 mL) in batches. The mixture was stirred at 0 ° C for 3 hours under a nitrogen atmosphere, followed by the addition of a solution of 5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester (20.1, 8.50 g, 50.8 mmol) in tetrahydrofuran (30 mL). The resulting mixture was then stirred at room temperature for 18 hours. The reaction mixture was quenched with a 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 (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (20.2, 12.0 g, 99%). LC-MS (ESI): m / z 238.1 [M+H] + .

[0616] To a solution of (E)-5-(3-ethoxy-3-oxoprop-1-ene-1-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (20.2, 12.0 g, 50.5 mmol) in ethanol (100 mL) was added Raney nickel (1.11 g, 5.06 mmol). The resulting mixture was degassed and backfilled with hydrogen three times, and then stirred at room temperature for 18 hours under a hydrogen atmosphere (1 atm). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 5-(3-ethoxy-3-oxopropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (20.3, 11.50 g, 95%) as a yellow oil. LC-MS (ESI): 240.1 [M+H] + .

[0617] To a mixture of 5-(3-ethoxy-3-oxopropyl)-1H-pyrrole-2-carboxylic acid ethyl ester (20.3, 11.5 g, 48.0 mmol), 4-dimethylaminopyridine (0.59 g, 4.81 mmol) and triethylamine (20 mL, 144 mmol) in acetonitrile (100 mL) was added di-tert-butyl dicarbonate (21.0 g, 96.2 mmol) 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 obtain 5-(3-ethoxy-3-oxopropyl)-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl) 2-ethyl ester (20.4, 10.0 g, 61%) as a white solid. LC-MS(ESI):m / z 240.3[M-100+H] + .

[0618] Palladium (1.00 g, 10% on carbon) was added to a solution of 5-(3-ethoxy-3-oxopropyl)-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl) 2-ethyl ester (20.4, 10.0 g, 29.4 mmol) in methanol (100 mL). The resulting mixture was degassed and backfilled with hydrogen three times, and then stirred at room temperature for 15 hours under a hydrogen atmosphere (1 atm). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 5-(3-ethoxy-3-oxopropyl) pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-ethyl ester (20.5, 9.00 g, 89%) as a yellow oil. LC-MS (ESI): 244.1 [M-100+H] + .

[0619] 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 hours. 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 obtain 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] + .

[0620] To a solution of 2-oxo-8-azabicyclo[3.2.1]octane-3,8-dicarboxylic acid 8-(tert-butyl) 3-ethyl ester (20.6, 5.00 g, 16.8 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (2.02 g, 50.4 mmol, 60% suspension in mineral oil) and N-phenyl-bis(trifluoromethanesulfonimide) (12.0 g, 33.6 mmol), and the mixture was stirred at 25 ° C for 12 hours. 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 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 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 product). LC-MS (ESI): m / z 374.0 [M-56+H] + .

[0621] 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)boric 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 for 3 hours under a nitrogen atmosphere. 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 obtain tert-butyl 2-chloro-4-fluoro-6-oxo-6,7,8,9,10,11-hexahydro-5H-8,11-aminocyclohepta[c]quinoline-12-carboxylate (20.8, 1.30 g) as a yellow solid. LC-MS (ESI): 323.0 [M-56+H] + .

[0622] To a solution of tert-butyl 2-chloro-4-fluoro-6-oxo-6,7,8,9,10,11-hexahydro-5H-8,11-poor aminocycloheptyl[c]quinoline-12-carboxylate (20.8, 1.30 g, 3.43 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (0.34 g, 8.58 mmol, 60% suspension in paraffin liquid) and N-phenyl-bis(trifluoromethanesulfonimide) (3.06 g, 8.58 mmol), 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 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 2-chloro-4-fluoro-6-(((trifluoromethyl)sulfonyl)oxy)-8,9,10,11-tetrahydro-7H-8,11-isocyanatocyclohepta[c]quinoline-12-carboxylate (20.9, 1.74 g, 99%) as a yellow oil. LC-MS (ESI): m / z 511.2 [M+H] + .

[0623] To a solution of tert-butyl 2-chloro-4-fluoro-6-(((trifluoromethyl)sulfonyl)oxy)-8,9,10,11-tetrahydro-7H-8,11-diaminocycloheptyl[c]quinoline-12-carboxylate (20.9, 1.00 g, 1.96 mmol) in tetrahydrofuran (10 mL) was added tetrakis(triphenylphosphine)palladium (0.23 g, 0.20 mmol), pyridine (1.6 mL, 19.6 mmol) and triethylsilane (2.28 g, 19.6 mmol). The mixture was stirred at 50 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture was 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 2-chloro-4-fluoro-8,9,10,11-tetrahydro-7H-8,11-aminocyclohepta[c]quinoline-12-carboxylate (20.10, 0.30 g, 38%) as a white solid. LC-MS (ESI): m / z 363.0 [M+H] + .

[0624] To a mixture of tert-butyl 2-chloro-4-fluoro-8,9,10,11-tetrahydro-7H-8,11-aminocyclohepta[c]quinoline-12-carboxylate (20.10, 300 mg, 0.83 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(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. for 15 hours under a nitrogen atmosphere. 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-aminocyclohepta[c]quinoline-12-carboxylate (20.11, 0.38 g, crude product). LC-MS (ESI): 455.1 [M+H] + .

[0625] 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-aminocyclohepta[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 obtain tert-butyl 2-(2,5-dichloropyrimidin-4-yl)-4-fluoro-8,9,10,11-tetrahydro-7H-8,11-isoaminocyclohepta[c]quinoline-12-carboxylate (20.12, 364 mg, crude) as a white solid. LC-MS (ESI): m / z 475.0 [M+H] + .

[0626] A mixture of tert-butyl 2-(2,5-dichloropyrimidin-4-yl)-4-fluoro-8,9,10,11-tetrahydro-7H-8,11-diaminocyclohepta[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 obtain 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-isocyanatocyclohepta[c]quinoline-12-carboxylate (20.13, 0.16 g) as a white solid. LC-MS (ESI): m / z 556.1 [M+H] + .

[0627] 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-aminocyclohepta[c]quinoline-12-carboxylate (20.13, 160 mg, 0.29 mmol) in dioxane (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 sodium bicarbonate solution (5 mL), and then 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-oxocyclohepta[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:

[0628] Isomer 1: (20a, 99.0% ee); retention time: 0.763 min. LC-MS (ESI): m / z 456.2 [M+H] + ; 1HNMR(500MHz,DMSO-d6)δ8.70(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 .6,5.7Hz,1H),2.05-1.90(m,2H),1.84(t,J=9.8Hz,1H),1.55(dt,J=20.0,9.7Hz,2H).

[0629] Isomer 2: (20b, 99.3% ee); retention time: 1.130 min; LC-MS (ESI): m / z 456.2 [M+H] + . 1 HNMR(500MHz,DMSO-d6)δ8.70(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).

[0630] Analytical separation method: column: CHIRALART Cellulose-SB, 4.6×50 mm, 3.0 um; mobile phase: A, MTBE (0.1% DEA), and B, EtOH; gradient: B 30%; flow rate: 1.67 mL / min; high pressure: 114 bar; column temperature: 25° C.; wavelength: 254 nm.

[0631] Preparative separation method: column: CHIRALART Cellulose-SB, 20×250 mm, 5 um; mobile phase: A, MTBE (10 mM NH 3 ), and B, EtOH; gradient: B 30%; flow rate: 20 mL / min; high pressure: 63 bar; column temperature: 25° C. wavelength: 256 nm / 234 nm; cycle time: about 12 minutes.

[0632] Example 21. Synthesis of (3S,4R)-4-((5-chloro-4-(7-fluoro-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridin-3,1'-cyclopropane]-9-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (21)

[0633]

[0634] To a suspension of tert-butyl (1-formylcyclopropyl)carbamate (10.0 g, 54.0 mmol) in tetrahydrofuran (200 mL) was added 2-(triphenyl-λ) 5 -phosphane subunit) ethyl acetate (21.1, 37.6 g, 108 mmol), 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 ground 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 obtain 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] + .

[0635] 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 backfilled with hydrogen three times, and then stirred at room temperature under a hydrogen atmosphere (1 atm) 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] + .

[0636] 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 hours. 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] + .

[0637] To a mixture of 3-(1-aminocyclopropyl)ethyl propionate hydrochloride (21.4, 8.56g, crude product) and potassium carbonate (12.2g, 88.4mmol) in acetonitrile (80mL) was added ethyl 2-bromoacetate (8.85g, 53.0mmol), 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 obtain 3-(1-((2-ethoxy-2-oxoethyl)amino)cyclopropyl)ethyl propionate (21.5, 5.74g) as a colorless oil. LC-MS (ESI): m / z 244.2[M+H] + .

[0638] 4-dimethylaminopyridine (144 mg, 1.18 mmol) and di-tert-butyl dicarbonate (6.18 g, 28.3 mmol) were added 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). 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 obtain 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] + .

[0639] 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 obtain 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] + .

[0640] 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) was added trifluoromethanesulfonic anhydride (1.70 mL, 10.1 mmol) dropwise at 0°C, and the mixture was stirred at 0°C for 30 minutes. 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] + .

[0641] 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)boric 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 for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 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] + .

[0642] 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) at 0°C was added trifluoromethanesulfonic anhydride (0.95 mL, 5.67 mmol) and the mixture was stirred at 0°C for 45 min. 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] + .

[0643] 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).

[0644] The mixture was stirred at 70 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 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 9-chloro-7-fluoro-1,4-dihydro-2H-spiro[benzo[c][2,6]naphthyridine-3,1'-cyclopropane]-2-carboxylic acid tert-butyl ester (21.11, 0.43 g, 83%) as a white solid. LC-MS (ESI): m / z 363.2[M+H] + .

[0645] 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'-di(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 for 2 hours under a nitrogen atmosphere. 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] + .

[0646] 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. for 3 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 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] + .

[0647] 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 layers were 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] + .

[0648] 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 solution (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]naphthyridin-3,1′-cyclopropane]-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] + . 1H NMR (500MHz, DMSO-d6) δ8.73(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),3.35(td,J=11.7,2.3Hz,1H),3.06(dd,J=11.1,9.6Hz,1H),2.88(s,2H ),2.01-1.92(m,1H),1.57-1.45(m,1H),0.69-0.62(m,2H),0.55-0.49(m,2H).

[0649] Example 22. (3S,4R)-4-((4-(4-chloro-8-fluoro-3-(2-hydroxypropan-2-yl)quinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-

[0650] Synthesis of pyran-3-ol (22)

[0651]

[0652] To a mixture of (4-chloro-8-fluoro-3-(2-hydroxypropane-2-yl)quinoline-6-yl)boric 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), tetrakis(triphenylphosphine)palladium (30.6 mg, 0.03 mmol) and potassium carbonate (48.7 mg, 0.35 mmol) were added. The resulting mixture was stirred at 90 ° C for 2 hours under a nitrogen atmosphere. 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 obtain 2-(4-chloro-6-(2-chloro-5-fluoropyrimidine-4-yl)-8-fluoroquinoline-3-yl)propane-2-ol (22.1, 50.0 mg, 76%) as a white solid. LC-MS(ESI):m / z 370.0[M+H] + .

[0653] 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] + . 1 H NMR (500MHz, DMSO-d6) δ9.44(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=5.5 Hz,1H),3.87-3.82(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).

[0654] Example 23. (3S,4R)-4-((5-fluoro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro

[0655] -Synthesis of 2H-pyran-3-ol (23)

[0656]

[0657] 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 obtain 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] + .

[0658] 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) δ9.13(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=5.4H z,1H),3.94-3.75(m,3H),3.59-3.48(m,1H),3.40-3.30(m,1H),3.13-3.0 5(m,1H),2.99(s,3H),2.10-1.94(m,1H),1.69(s,6H),1.57-1.47(m,1H).

[0659] 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)

[0660]

[0661] At 0°C, sodium ethoxide (50.1 mL, 133 mmol, 20% in ethanol) was added dropwise to a solution of 5,5-dimethyltetrahydropyrrole-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), and the mixture was stirred at 80°C for 48 hours. The resulting mixture was cooled to room temperature, diluted with water (50 mL) and adjusted to pH 3-4 with 2N 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 then 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.

[0662] At -78 ° C, trifluoromethanesulfonic anhydride (3.95 mL, 23.4 mmol) was added dropwise to a solution of 5-hydroxy-2,2-dimethyl-6-oxo-1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl ester (24.2, 5.00 g, crude product) and N,N-diisopropylethylamine (11.6 mL, 70.3 mmol) in dichloromethane (100 mL), and the mixture was stirred at -78 ° C for 1 hour and then warmed to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with dichloromethane (50 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 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).

[0663] 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 for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure and the residue was ground with water (30 mL) and ethyl acetate (30 mL). The suspension was filtered and the filter cake was washed with water (10 mL) and ethyl acetate (20 mL) in sequence. The filter 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] + .

[0664] A mixture of 9-chloro-7-fluoro-3,3-dimethyl-2,3,4,6-tetrahydrobenzo [c] [2,6] naphthyridine-1,5-dione (24.4, 1.40 g, 4.75 mmol) and phosphorus oxychloride (10 mL) was stirred at 100 ° C for 16 hours under a nitrogen atmosphere. 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 sodium bicarbonate aqueous solution, and extracted with dichloromethane (50 mL × 2). The combined organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5,9-dichloro-7-fluoro-3,3-dimethyl-3,4-dihydrobenzo [c] [2,6] naphthyridine-1 (2H) -one (24.5, 1.40 g, crude product) as a yellow solid. LC-MS(ESI):m / z 313.3[M+H] + .

[0665] A mixture of 5,9-dichloro-7-fluoro-3,3-dimethyl-3,4-dihydrobenzo[c][2,6]naphthyridine-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 a crude product, which was ground 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] + .

[0666] At 0 ° C, 9-chloro-7-fluoro-3,3-dimethyl-3,4-dihydrobenzo [c] [2,6] naphthyridine-1 (2H) -one (24.6, 100 mg, 0.36 mmol) was added to a solution of tetrahydrofuran (3 mL) in bis (cyclopentadiene) zirconium chloride (463 mg, 1.80 mmol) in batches, and the mixture was stirred at 0 ° C for 1 hour. Methanol (10 mL) was then added to the reaction mixture, followed by sodium borohydride (57.0 mg, 1.51 mmol) in batches 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 subjected to 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] + .

[0667] 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'-di(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)phosphine (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 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 layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain 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, two-step yield 32%) as a brown solid. LC-MS (ESI): m / z 361.2[M+H] + .

[0668] 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. The reaction mixture was cooled to room temperature, and then methanol (200 μL) and sodium borohydride (1.00 mg, 0.03 mmol) were added in sequence. The resulting mixture was stirred at room temperature for another 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 for two steps) as a yellow solid. LC-MS (ESI): m / z 442.3 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.73(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,2H),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).

[0669] Example 25. (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-2-methylquinolin-6-yl)pyrimidine-2-

[0670] Synthesis of (4-(2-amino)tetrahydro-2H-pyran-3-ol (60)

[0671]

[0672] Under nitrogen atmosphere, at 0 ° C, methyl-d3-magnesium iodide (64 mL, 64 mmol, 1.0 M in diethyl ether) was added dropwise to a solution of 6-bromo-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester (5.1, 4.00 g, 12.8 mmol) in anhydrous tetrahydrofuran (80 mL), and the mixture was stirred at 25 ° C for 3 hours under nitrogen atmosphere. The reaction mixture was extracted with saturated ammonium chloride solution (20 mL), diluted with water (50 mL) and extracted with ethyl acetate (50 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 obtain 2- (6-bromo-8-fluoro-2-methylquinoline-3-yl) propane-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] + .

[0673] A mixture of 2-(6-bromo-8-fluoro-2-methylquinolin-3-yl)propane-1,1,1,3,3,3-d6-2-ol (60.1, 2.20 g, 7.23 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-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-dichloropalladium(II) (525 mg, 0.72 mmol) in dioxane (40 mL) was stirred at 90° C. for 3 hours under a nitrogen atmosphere. 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] + .

[0674] 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 obtain 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] + .

[0675] A mixture of 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-2-methylquinolin-3-yl)propane-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 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-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] + . 1 H NMR (400MHz, DMSO-d6) δ8.46(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 ),3.89-3.79(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).

[0676] Example 26. (3S,4R)-4-((5-chloro-4-(4-ethyl-8-fluoro-3-(2-hydroxypropan-2-yl)cinnolin-6-yl)pyrimidin-2-yl)amino)tetrahydro

[0677] -Synthesis of 2H-pyran...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in: L 1 is an optionally substituted phenylene, an optionally substituted 5- or 6-membered heteroarylene, an optionally substituted 4-8-membered heterocyclylene, or an optionally substituted C 3-8 Carbocyclylene; R 1 is hydrogen, OH, NH2, NHCH3 or N(CH3)2; X is N or CR 10 ; R 2 is an optionally substituted ring system selected from a 10-membered heteroaryl, a 9-12-membered bicyclic heterocycle, or a 12-16-membered heteroaryl or a heterocyclic structure having three or more rings, wherein the ring system includes at least one phenyl or heteroaryl ring, and wherein R 2 is attached to the remainder of Formula I via a ring atom of the phenyl or heteroaryl portion of the ring system, provided that the 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 NR 12 R 13 、C(O)NR 12 R 13 、COOR A , COR 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 4-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; R 4 is hydrogen, deuterium, halogen (eg, F), optionally substituted C 1-6 Alkyl, or NR 12 R 13 ; in: R 10 is hydrogen, halogen (eg, 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 4-10 membered heterocyclyl; or an oxygen protecting group; R 12 and R 13 Each of the following, at each occurrence, is independently 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 4-10 membered heterocyclyl; or a nitrogen protecting group; or R 12 and R 13 may be linked to form an optionally substituted 4-10 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 (eg, 5- or 6-membered heteroaryl), optionally substituted 4-10 membered heterocyclyl; or an oxygen protecting group; and R B is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted heteroaryl (eg, 5- or 6-membered heteroaryl).

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound or a pharmaceutically acceptable salt thereof has a structure according to Formula A: in: Q is (1)O； (2)NR 14 , where R 14 It is hydrogen, G A 、SO2G A 、SO2NG B G C 、S(O)(NH)G A , COG A ,COOG A , or C(O)NG B G C ; (3)CR 15 R 16 , where R 15 and R 16 are joined together with the carbon atom to which they are attached to form an optionally substituted 4-6 membered heterocyclic ring having 1 or 2 ring heteroatoms independently selected from O and N; or (4) does not exist; r1 is 1, 2, or 3; and r2 is 0, 1, or 2; When valency permits, n is 0, 1, 2, 3 or 4; and (i)R 100 At each occurrence, is independently selected from halogen (e.g., F or Cl), CN, OH, COOH, G A , OG A NG B G C NG B G C SO2G A NG B G C SO2NG B G C NG B G C S(O)(NH)G A NG B G C COG A NG B G C COOG A NG B G C C(O)NG B G C 、SO2G A 、SO2NG B G C 、S(O)(NH)G A , COG A ,COOG A , or C(O)NG B G C ;or (ii) R 100 Two instances of are joined together with one or more intervening atoms to form an optionally substituted ring, such as an optionally substituted 3-6 membered ring, and any remaining R 100 as defined in (i) at each occurrence; in: G A is independently at each occurrence an optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted phenyl, optionally substituted heteroaryl (eg, 5- or 6-membered heteroaryl), or optionally substituted 4-10 membered heterocyclyl; and G B and G C Each of the following, at each occurrence, is independently 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 4-10 membered heterocyclyl; or a nitrogen protecting group; or G B and G C Can be linked to form an optionally substituted 4-10 membered heterocyclyl or 5- or 6 membered heteroaryl.

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

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2, and R 100 is independently selected at each occurrence from F, Cl, CN, OH, C optionally substituted with F 1-4 alkyl, optionally substituted with F 1-4 alkoxy, and C optionally substituted by F 1-4 Heteroalkyl.

5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1, and R 100 It is F, Cl, CN, OH, methyl, fluorine-substituted methyl such as CF3, methoxy, or fluorine-substituted methoxy.

6. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is characterized by having formula A-1 or A-2: in: R 17 yes (1)C 1-4 Alkyl, which is optionally substituted with 1-3 substituents independently selected from deuterium, F, and OH, such as CHF2, CF3, etc.; (2) phenyl, pyridyl, or pyrimidinyl, each of which is optionally substituted with 1-3 independently selected from deuterium, halogen, CN, OH, C optionally substituted with F 1-3 alkyl, or C optionally substituted by F 1-3 Substitution of the alkoxy group; or (3) 5-membered heteroaryl, which is optionally substituted by 1-3 independently selected from deuterium, halogen, CN, OH, C optionally substituted by F 1-3 alkyl, or C optionally substituted by F 1-3 The substituents of the alkoxy group are substituted.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 17 Selected from:

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L in Formula I 1 -R 1 Selected from: or L in Formula I 1 -R 1 Selected from:

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

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 2 is a 10-membered bicyclic heteroaryl having 1-4 ring nitrogen atoms, such as quinolyl, naphthyridinyl, etc., which is optionally substituted by one or more (e.g., 1, 2, or 3) independently selected from halo (e.g., F), CN, G 1 , OH, COOH, C(O)-G 1 , OG 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 , OG 2 NH(G 2 )、N(G 1 )(G 2 )、C(O)-NH(G 2 ), and C(O)-N(G 1 )(G 2 ) is substituted by a substituent, Among them G 1 is independently at each occurrence optionally replaced by 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 1-4 Alkyl, or optionally 1-3 independently selected from F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 Cycloalkyl; Among them G 2 is independently at each occurrence a 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, phenyl, or a 5- or 6 membered heteroaryl, each of which is optionally substituted by 1-3 independently selected from oxo (if applicable), halo (e.g. F), CN, G 1 ,OH,OG 1 、NH2、NH(G 1 ), and N(G 1 )(G 1 ) is substituted with a substituent; and Wherein the two optional substituents of the 10-membered bicyclic heteroaryl group, together with one or more intervening atoms, may be optionally linked to form a fused ring structure.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 2 With the structure according to M-1: in: J 1 and J 2 Independently N or CR 30 , where R 30 is independently at each occurrence hydrogen, halogen, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 heteroalkyl; R 20 is hydrogen, halogen (such as F or Cl), CN, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 heteroalkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl); R 21 , R 22 and R 23 Each independently represents: (1) hydrogen or deuterium; (2) halogen (such as F or Cl), (3) CN, (4) optionally substituted by 1-3 each independently representing F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) optionally substituted by 1-3 groups each independently being oxo, halo (eg, F), OH, NH2, C 1-4 alkyl, or C optionally substituted by F 1-4 a 3-6 membered ring structure substituted with a substituent of the heteroalkyl group (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl group), or R 21 and R 22 Together with the intervening atoms, they form a 5-8 membered ring (e.g., a 5-7 membered carbocyclic or heterocyclic ring), which is optionally substituted with 1-3 atoms, each independently oxo, deuterium, halo (e.g., F), OH, NH2, C 1-4 alkyl, or C optionally substituted by F 1-4 The substituent of heteroalkyl is substituted, and R 23 As defined above; or R 22 and R 23 Together with the intervening atoms, they form a 5-8 membered ring (e.g., a 5-7 membered carbocyclic ring, an aryl ring, a heteroaryl ring, or a heterocyclic ring), which is optionally substituted with 1-3 atoms, each independently oxo, deuterium, halo (e.g., F), OH, NH2, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 The substituent of heteroalkyl is substituted, and R 21 As defined above; Preferably, R 21 , R 22 , and R 23 At least one of the R 21 , R 22 and R 23 Only one of them contains a hydrogen bond donor, or R 21 and R 22 , or R 22 and R 23 The formed ring structure contains a hydrogen bond donor.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein J 1 Yes CR 30 , and R 30 It's hydrogen.

13. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein J 1 It is N.

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

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

16. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 2 Having a structure according to M-1-1: in: R 21 , R 22 and R 23 Each independently represents: (1) hydrogen or deuterium; (2) halogen (such as F or Cl), (3) CN, (4) optionally substituted by 1-3 each independently representing F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) optionally substituted by 1-3 groups each independently being oxo, halo (eg, F), OH, NH2, C 1-4 alkyl, or C optionally substituted by F 1-4 The substituents of the heteroalkyl group are substituted 3-6 membered ring structures (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl).

17. The compound or pharmaceutically acceptable salt thereof according to claim 11 or 16, wherein the compound is a compound having formula I-1:

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

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

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 11 to 19, wherein R 21 is hydrogen, deuterium, halogen (such as F or Cl), C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 Heteroalkyl, preferably, R 21 is hydrogen, deuterium, F, or methyl.

21. The compound or pharmaceutically acceptable salt thereof according to any one of claims 11 to 19, wherein R 21 is OH, NH2, or NH(C 1-4 Alkyl) substituted C 1-4 alkyl.

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 11 to 19, wherein R 21 yes 23. A compound according to any one of claims 11 to 19 or a pharmaceutically acceptable salt thereof, wherein R 21 is a 4-6 membered heterocyclic ring having 1 or 2 ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc., wherein the 4-6 membered heterocyclic ring is optionally substituted by 1-3 each independently being oxo, F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 alkyl) substituent.

24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 11 to 19, wherein R 21 is azetidinyl or pyrrolidinyl, e.g.

25. The compound or pharmaceutically acceptable salt thereof according to any one of claims 11 to 19, wherein R 21 is a 5-membered heteroaryl ring having 2-4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., wherein the 5-membered heteroaryl ring is optionally substituted by 1-3 each independently being F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 alkyl) substituent.

26. The compound or pharmaceutically acceptable salt thereof according to any one of claims 11 to 19, wherein R 21 is imidazolyl or pyrazolyl, which is optionally substituted by one or two C 1-4 Alkyl groups, such as methyl groups, such as replace.

27. A compound as described in any one of claims 11 to 26 or a pharmaceutically acceptable salt thereof, wherein R 22 is hydrogen, halogen (such as F or Cl), C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 Heteroalkyl.

28. A compound according to any one of claims 11 to 26 or a pharmaceutically acceptable salt thereof, wherein R 22 is OH, NH2, or NH(C 1-4 Alkyl) substituted C 1-4 Alkyl, or R 22 is OH, NH2, or NH(C 1-4 Alkyl) substituted C 3-6 Cycloalkyl.

29. The compound or pharmaceutically acceptable salt thereof of any one of claims 11 to 26, wherein R 22 yes or R 22 yes or R 22 yes or R 22 yes or R 22 yes 30. The compound or pharmaceutically acceptable salt thereof of any one of claims 11-26, wherein R 22 is a 4-6 membered heterocyclic ring having 1 or 2 ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, etc., wherein the 4-6 membered heterocyclic ring is optionally substituted by 1-3 each independently being oxo, F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 alkyl) substituent.

31. A compound as described in any one of claims 11-26 or a pharmaceutically acceptable salt thereof, wherein R 22 is azetidinyl or pyrrolidinyl, e.g. or R 22 yes 32. A compound as described in any one of claims 11-26 or a pharmaceutically acceptable salt thereof, wherein R 22 is a 5-membered heteroaryl ring having 2-4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., wherein the 5-membered heteroaryl ring is optionally substituted by 1-3 each independently being F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 alkyl) is substituted by a substituent, preferably, R 22 is imidazolyl or pyrazolyl, which is optionally substituted by one or two C 1-4 Alkyl groups, such as methyl groups, such as replace.

33. A compound as described in any one of claims 11 to 19 or a pharmaceutically acceptable salt thereof, wherein R 21 and R 22 Together with the intervening atoms, they are linked together to form a 5- or 6-membered ring, preferably a 5- or 6-membered carbocyclic ring, which is substituted by 1-3 atoms each independently being F, OH, NH2, C 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 alkyl), preferably one of the one or more substituents comprises a hydrogen bond donor, such as OH, NH2, or NH(C 1-4 alkyl).

34. A compound as described in any one of claims 11-33 or a pharmaceutically acceptable salt thereof, wherein R 23 is hydrogen, deuterium, halogen (such as F or Cl), C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 Heteroalkyl, such as N(CH3)2, preferably, R 23 It is hydrogen, deuterium, F, Cl or methyl.

35. A compound as described in any one of claims 11-33 or a pharmaceutically acceptable salt thereof, wherein R 23 is OH, NH2, or NH(C 1-4 Alkyl) substituted C 1-4 alkyl.

36. A compound as described in any one of claims 11-33 or a pharmaceutically acceptable salt thereof, wherein R 23 yes 37. A compound as described in any one of claims 11-33 or a pharmaceutically acceptable salt thereof, wherein R 23 is a 4-6 membered heterocyclic ring having 1 or 2 ring heteroatoms, such as azetidinyl, pyrrolidinyl, piperidinyl, etc., wherein the 4-6 membered heterocyclic ring is optionally substituted by 1-3 each independently being oxo, F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 alkyl) substituent.

38. A compound as described in any one of claims 11-33 or a pharmaceutically acceptable salt thereof, wherein R 23 is azetidinyl or pyrrolidinyl, e.g.

39. A compound as described in any one of claims 11-33 or a pharmaceutically acceptable salt thereof, wherein R 23 is a 5-membered heteroaryl ring having 2-4 ring heteroatoms, such as imidazolyl, pyrazolyl, etc., wherein the 5-membered heteroaryl ring is optionally substituted by 1-3 each independently being F, OH, NH2, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 alkyl) is substituted by a substituent, preferably, R 23 is imidazolyl or pyrazolyl, which is optionally substituted by one or two C 1-4 Alkyl groups, such as methyl groups, such as replace.

40. A compound as described in any one of claims 11-26 or a pharmaceutically acceptable salt thereof, wherein R 22 and R 23 Together with the intervening atoms, they are linked together to form a 5- or 6-membered ring, preferably a 5- or 6-membered carbocyclic ring, which is substituted by 1-3 atoms each independently being F, OH, NH2, C 1-4 alkyl, optionally substituted with F 1-4 Alkoxy, or NH(C 1-4 alkyl), preferably one of the one or more substituents comprises a hydrogen bond donor, such as OH, NH2, or NH(C 1-4 alkyl).

41. A compound as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 Having a structure according to M-2 or M-5: in: J 1 and J 2 Independently N or CR 30 , where R 30 is independently at each occurrence hydrogen, halogen, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 heteroalkyl; Ring C is a heterocyclic or heteroaryl ring, which is optionally replaced by R 110 1-5 instances of substituted, i.e., when valence permits, p is 0-5, wherein R 110 is independently at each occurrence (1) oxo, (2) halogen (eg, F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) R 110 The two examples are linked together with one or more intervening atoms to form a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle), which is optionally substituted with 1-3 each independently being oxo, halo (e.g., F), OH, NH2, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 Substitution of heteroalkyl groups, J 3 and J 4 N, NR independently 31 , CR 32 R 33 , or CR 34 ,in R 31 is independently at each occurrence hydrogen, C optionally substituted with F 1-4 alkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl), R 32 and R 33 Each of the following, at each occurrence, is independently (1) hydrogen or deuterium, (2) a halogen (e.g., F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) an optionally substituted 3-6 membered ring structure (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl); or (7) R 32 and R 33 , which are linked together with the carbon atoms to which they are commonly bonded to form a carbonyl (CO) or a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, or a 4-6 membered heterocycle), which is optionally substituted by 1-3 groups, each independently being oxo, halo (e.g., F), OH, NH2, C optionally substituted by F 1-4 alkyl, or C optionally substituted by F 1-4 Substitution of a heteroalkyl group; or R 32 Two instances of, or R 32 An example and R 100 An example of an alkyl radical, connected together with one or more intervening atoms to form a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle), which ring structure is optionally substituted by 1-3 groups, each independently being oxo, halo (e.g., F), OH, NH2, C optionally substituted by F 1-4 alkyl, or C optionally substituted by F 1-4 Substitution of heteroalkyl groups; R 34 is independently at each occurrence (1) hydrogen, (2) halogen (e.g., F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) an optionally substituted 3-6 membered ring structure (eg, cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl); and R 20A and R 21A are each independently hydrogen, deuterium, halogen (such as F or Cl), CN, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 heteroalkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl).

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

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

44. The compound of claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein J 1 It is N.

45. A compound as described in any one of claims 41-44 or a pharmaceutically acceptable salt thereof, wherein J 2 Yes CR 30 , and R 30 It's hydrogen.

46. ​​A compound as described in any one of claims 41-44 or a pharmaceutically acceptable salt thereof, wherein J 2 It is N.

47. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having formula I-2:

48. A compound as described in any one of claims 41-47 or a pharmaceutically acceptable salt thereof, wherein R 20A is hydrogen, halogen, or C 1-4 alkyl.

49. A compound as described in any one of claims 41-47 or a pharmaceutically acceptable salt thereof, wherein R 20A is hydrogen, F, Cl, methyl, or ethyl, preferably, R 20A It's F.

50. A compound as described in any one of claims 41-49 or a pharmaceutically acceptable salt thereof, wherein R 21A is hydrogen, deuterium, halogen, or C 1-4 alkyl.

51. A compound as described in any one of claims 41-49 or a pharmaceutically acceptable salt thereof, wherein R 21A is hydrogen, deuterium, F, Cl, methyl, or ethyl, preferably, R 21A It is hydrogen, deuterium, or methyl.

52. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 41-51, wherein p is 0, or p is 1, and R 110 It is OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 Alkyl), or C 1-4 alkyl.

53. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 41-51, wherein p is 2, wherein R 110 C independently at each occurrence 1-4 Alkyl (e.g. methyl, ethyl); or two R 110 With one or more intervening atoms joined together to form a 3-6 membered ring, for example a cyclopropyl ring.

54. A compound as described in any one of claims 41-53 or a pharmaceutically acceptable salt thereof, wherein J 3 YesNR 31 , and R 31 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl).

55. A compound as described in any one of claims 41-53 or a pharmaceutically acceptable salt thereof, wherein J 3 It is N.

56. A compound as described in any one of claims 41-53 or a pharmaceutically acceptable salt thereof, wherein J 3 Yes CR 34 , and R 34 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl).

57. A compound as described in any one of claims 41-53 or a pharmaceutically acceptable salt thereof, wherein J 3 Yes CR 32 R 33 , and R 32 is hydrogen, deuterium, F, or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen, deuterium, F, or C 1-4 Alkyl (eg, methyl or ethyl), such as J 3 It is CH2, CD2, CF2, CH(CH3), or C(CH3)2.

58. A compound as described in any one of claims 41-53 or a pharmaceutically acceptable salt thereof, wherein J 3 Yes CR 32 R 33 , and R 32 and R 33 Together with the carbon atoms to which they are simultaneously bonded, they form a 3-4 membered ring, for example cyclopropyl.

59. A compound as described in any one of claims 41-58 or a pharmaceutically acceptable salt thereof, wherein J 4 YesNR 31 , and R 31 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl).

60. A compound as described in any one of claims 41-58 or a pharmaceutically acceptable salt thereof, wherein J 4 It is N.

61. A compound as described in any one of claims 41-58 or a pharmaceutically acceptable salt thereof, wherein J 4 Yes CR 34 , and R 34 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl).

62. A compound as described in any one of claims 41-58 or a pharmaceutically acceptable salt thereof, wherein J 4 Yes CR 32 R 33 , and R 32 is hydrogen, deuterium, F, or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen, deuterium, F, or C 1-4 Alkyl (eg, methyl or ethyl), such as J 4 It is CH2, CD2, CF2, CH(CH3), or C(CH3)2.

63. A compound as described in any one of claims 41-58 or a pharmaceutically acceptable salt thereof, wherein J 4 Yes CR 32 R 33 , and R 32 and R 33 Together with the carbon atoms to which they are simultaneously bonded, they form a 3-4 membered ring, such as cyclopropyl; or J 4 It is C(O).

64. A compound as described in any one of claims 41-63, or a pharmaceutically acceptable salt thereof, wherein, if applicable, R 2 is characterized by having a structure according to 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: in: When valence permits, p1 is 0, 1, 2, or 3; and R 111 is hydrogen or R 110 ,and If applicable, these variables J 1 , J 2 , R 20A , R 21A , R 31 , R 32 , R 33 , R 34 , and R 110 As defined in any one of claims 39 to 60.

65. The compound of claim 64 or a pharmaceutically acceptable salt thereof, wherein, if applicable, R 2 is characterized by having a structure according to 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:

66. The compound or pharmaceutically acceptable salt thereof of claim 64 or 65, wherein in F-1 or F-2 (or a subformula thereof), p1 is 0, or p1 is 1, and R 110 It is C 1-4 alkyl.

67. The compound or pharmaceutically acceptable salt thereof of claim 64 or 65, wherein in F-1 or F-2 (or a subformula thereof), p is 2, wherein R 110 C independently at each occurrence 1-4 Alkyl (e.g. methyl, ethyl); or two R 110 With one or more intervening atoms joined together to form a 3-6 membered ring, for example a cyclopropyl ring.

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

69. The compound of claim 64 or 65, or a pharmaceutically acceptable salt thereof, wherein in F-4, F-5, F-6, or F-7 (or a subformula thereof), R 111 is NH2 or NH(C 1-4 alkyl).

70. A compound as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 Having a structure according to M-3 or M-4: in: J 1 and J 2 Independently N or CR 30 , where R 30 is independently at each occurrence hydrogen, halogen, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 heteroalkyl; Ring C is a heterocyclic or heteroaryl ring, which is optionally replaced by R 110 1-5 instances of substituted, i.e., when valence permits, p is 0-5, wherein R 110 is independently at each occurrence (1) oxo, (2) halogen (eg, F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) R 110 The two examples are linked together with one or more intervening atoms to form a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle), which is optionally substituted with 1-3 each independently being oxo, halo (e.g., F), OH, NH2, C optionally substituted with F 1-4 alkyl, or C optionally substituted by F 1-4 Substitution of heteroalkyl groups, U is O or C(=O); W and V are independently C, N, or CR 34 ; t is 0, 1, 2, or 3, and each Z is independently O, N, NR 31 , CR 32 R 33 , or CR 34 ; wherein the bond between W and V, W and Z, or two consecutive Zs is a single bond or a double bond when valence permits, J 3 and J 4 N, NR independently 31 , CR 32 R 33 , or CR 34 ,in R 31 is independently at each occurrence hydrogen, C optionally substituted with F 1-4 alkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl), R 32 and R 33 Each of the following, at each occurrence, is independently (1) hydrogen, (2) halogen (e.g., F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) an optionally substituted 3-6 membered ring structure (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl); or (7) R 32 and R 33 , which are linked together with the carbon atoms to which they are commonly bonded to form a carbonyl (CO) or a 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, or a 4-6 membered heterocycle), which is optionally substituted by 1-3 groups, each independently being oxo, halo (e.g., F), OH, NH2, C optionally substituted by F 1-4 alkyl, or C optionally substituted by F 1-4 Substitution of heteroalkyl groups; R 34 is independently at each occurrence (1) hydrogen, (2) halogen (e.g., F or Cl), (3) OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 alkyl), (4) optionally substituted by 1-3 each independently being F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl); or J 3 and R 110 An instance of J 4 and R 110 An instance of is linked together with one or more intervening atoms to form a ring structure; R 20A is hydrogen, halogen (such as F or Cl), CN, C optionally substituted by F 1-4 alkyl, optionally substituted with F 1-4 heteroalkyl, or an optionally substituted 3-6 membered ring structure (e.g., cyclopropyl, cyclobutyl, a 4-6 membered heterocycle, or a 5 membered heteroaryl); and R 22A and R 23A are each independently: (1) hydrogen; (2) halogen (e.g., F or Cl); (3) CN; (4) optionally substituted by 1 to 3 each independently of the other: F, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)(C 1-4 Alkyl), NH(C 3-6 Cycloalkyl), N(C 1-4 Alkyl)(C 3-6 Cycloalkyl), or N(C 3-6 Cycloalkyl)(C 3-6 The substituents of cycloalkyl) are substituted with C 1-4 Alkyl, (5) C optionally substituted by F 1-4 heteroalkyl, or (6) optionally substituted by 1-3 groups each independently being oxo, halo (eg, F), OH, NH2, C 1-4 alkyl, optionally substituted with F 1-4 The substituents of the heteroalkyl group are substituted 3-6 membered ring structures (eg, cyclopropyl, cyclobutyl, 4-6 membered heterocycle, or 5 membered heteroaryl).

71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein ring C is a heterocycle having 1 or 2 ring heteroatoms, such as a 5- or 6-membered heterocycle having 1 or 2 ring nitrogen atoms; or ring C is a 5-membered heteroaryl ring having 1 or 2 ring heteroatoms.

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

73. The compound of claim 70 or 71, or a pharmaceutically acceptable salt thereof, wherein J 1 It is N.

74. A compound as described in any one of claims 70-73, or a pharmaceutically acceptable salt thereof, wherein J 2 Yes CR 30 , and R 30 It's hydrogen.

75. A compound as described in any one of claims 70-73, or a pharmaceutically acceptable salt thereof, wherein J 2 It is N.

76. The compound of claim 70 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having Formula I-3 or I-4:

77. A compound as described in any one of claims 70-76, or a pharmaceutically acceptable salt thereof, wherein R 20A is hydrogen, halogen, or C 1-4 alkyl.

78. A compound as described in any one of claims 70-76, or a pharmaceutically acceptable salt thereof, wherein R 20A is hydrogen, F, Cl, methyl, or ethyl.

79. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 70-78, wherein p is 0, or p is 1, and R 110 It is OH, NH2, NH(C 1-4 alkyl), or N(C 1-4 Alkyl)(C 1-4 Alkyl), or C 1-4 alkyl.

80. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 70-78, wherein p is 2, wherein R 110 C independently at each occurrence 1-4 Alkyl (e.g. methyl, ethyl); or two R 110 With one or more intervening atoms joined together to form a 3-6 membered ring, for example a cyclopropyl ring.

81. A compound as described in any one of claims 70-80 or a pharmaceutically acceptable salt thereof, wherein J 3 YesNR 31 , and R 31 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl).

82. A compound as described in any one of claims 70-80 or a pharmaceutically acceptable salt thereof, wherein J 3 It is N.

83. A compound as described in any one of claims 70-80 or a pharmaceutically acceptable salt thereof, wherein J 3 Yes CR 34 , and R 34 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl).

84. A compound as described in any one of claims 70-80, or a pharmaceutically acceptable salt thereof, wherein J 3 Yes CR 32 R 33 , and R 32 is hydrogen or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl), such as J 3 It is CH2, CH(CH3), or C(CH3)2.

85. A compound as described in any one of claims 70-80, or a pharmaceutically acceptable salt thereof, wherein J 3 Yes CR 32 R 33 , and R 32 and R 33 Together with the carbon atoms to which they are simultaneously bonded, they form a 3-4 membered ring, for example cyclopropyl.

86. A compound as described in any one of claims 70-85, or a pharmaceutically acceptable salt thereof, wherein J 4 YesNR 31 , and R 31 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl).

87. A compound as described in any one of claims 70-85, or a pharmaceutically acceptable salt thereof, wherein J 4 It is N.

88. A compound as described in any one of claims 70-85, or a pharmaceutically acceptable salt thereof, wherein J 4 Yes CR 34 , and R 34 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl).

89. A compound as described in any one of claims 70-85 or a pharmaceutically acceptable salt thereof, wherein J 4 Yes CR 32 R 33 , and R 32 is hydrogen or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl), such as J 4 It is CH2, CH(CH3), or C(CH3)2.

90. A compound as described in any one of claims 70-85 or a pharmaceutically acceptable salt thereof, wherein J 4 Yes CR 32 R 33 , and R 32 and R 33 Together with the carbon atoms to which they are simultaneously bonded, they form a 3-4 membered ring, for example cyclopropyl.

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

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

93. A compound as described in any one of claims 70-92, or a pharmaceutically acceptable salt thereof, wherein t is 1 or 2.

94. A compound as described in any one of claims 70-93, or a pharmaceutically acceptable salt thereof, wherein Z is independently CR at each occurrence. 32 R 33 , and R 32 is hydrogen or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl), for example, Z is CH2, CH(CH3), or C(CH3)2.

95. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 70-93, wherein an example of Z is CR 32 R 33 , where R 32 and R 33 Together with the carbon atoms to which they are simultaneously bonded, to form a 3-4 membered ring, such as cyclopropyl; and any remaining instances of Z are independently CR 32 R 33 , where R 32 is hydrogen or C 1-4 alkyl (eg, methyl or ethyl), and R 33 is hydrogen or C 1-4 Alkyl (eg, methyl or ethyl), for example, the remaining instances of Z are independently CH2, CH(CH3), or C(CH3)2.

96. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 70-93, wherein W is C, and Z directly connected to W is CR 34 , where R 34 is hydrogen or C 1-4 An alkyl group (eg, methyl or ethyl) and the bond between Z and W is a double bond.

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

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

99. A compound as described in any one of claims 70-90 or a pharmaceutically acceptable salt thereof, wherein R 2 Having a structure according to 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:

100. The compound of claim 99 or a pharmaceutically acceptable salt thereof, wherein R 2 Having a structure according to 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: in: R 111 is hydrogen or R 110 .

101. A compound as described in any one of claims 70-100, or a pharmaceutically acceptable salt thereof, wherein R 22A It is hydrogen, C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 Heteroalkyl.

102. A compound as described in any one of claims 70-100, or a pharmaceutically acceptable salt thereof, wherein R 22A is OH, NH2, or NH(C 1-4 Alkyl) substituted C 1-4 alkyl.

103. A compound as described in any one of claims 70-102, or a pharmaceutically acceptable salt thereof, wherein R 23A It is hydrogen, C 1-4 Alkyl (eg, methyl or ethyl) or C having 1 or 2 heteroatoms which are independently oxygen or nitrogen 1-4 Heteroalkyl.

104. A compound as described in any one of claims 70-102, or a pharmaceutically acceptable salt thereof, wherein R 23A is OH, NH2, or NH(C 1-4 Alkyl) substituted C 1-4 alkyl.

105. A compound as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: or R 2 Selected from:

106. A compound as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: or R 2 Selected from 107. A compound as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: or R 2 Selected from or R 2 Selected from:

108. A compound as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from:

109. A compound as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from:

110. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 9, wherein R 2 Selected from: or R 2 Selected from 111. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 110, wherein R 3 is hydrogen, F, Cl, Br, C optionally substituted by F and / or deuterium 1-4 Alkyl (e.g., methyl, CD3, ethyl, CHF2, CF2CH3, CF2CF3, CH2CH2F, CH2CF2H, or CF3), or CN.

112. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 110, wherein R 3 It is C 3-6 Cycloalkyl, 4-6 membered heterocyclyl having 1-2 ring heteroatoms independently selected from N, O and S, or 5-6 membered heteroaryl having 1-4 ring heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1-3 independently selected from 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 ) is substituted by a substituent, wherein G 1 is optionally replaced by 1-3 independently selected from deuterium, F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 1-4 alkyl, or optionally substituted by 1-3 independently selected from deuterium, F, CN, OH, and C 1-4 Substituents of heteroalkyl substituted C 3-6 Cycloalkyl.

113. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 110, wherein R 3 Selected from:

114. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 113, wherein R 4 It is hydrogen or deuterium.

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

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

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 cancer and thyroid cancer.

119. 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. The method of claim 117, wherein the cancer is breast cancer selected from the group consisting of: 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. The method of claim 117, wherein the cancer is breast cancer selected from the group consisting of endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition.

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

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

124. The method of any one of claims 117-123, wherein the cancer is mediated by a CDK (eg, CDK4).

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