Amino heteroaryl kinase inhibitors

Abstract

Provided herein are novel compounds (e.g., of Formula I or II), pharmaceutical compositions, and methods of use related to cyclin-dependent kinases (CDKs). The compounds herein are generally CDK2 inhibitors, which can be used to treat a variety of diseases or disorders, such as cancer.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to International Application No. PCT / CN2021 / 081236, filed on March 17, 2021, and International Application No. PCT / CN2020 / 132454, filed on November 27, 2020, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0003] In various embodiments, this disclosure generally relates to novel heteroaryl compounds, compositions comprising the same, methods of their preparation and use, for example, for inhibiting cyclin-dependent kinases and / or for treating or preventing the various diseases or disorders described herein. Background Technology

[0004] Cyclin-dependent kinases (CDKs) are a family of serine / threonine protein kinases that regulate cell cycle progression. Among CDKs, CDK2 is a key driver of the transition from late G1 to S and G2 phases. In late G1, CDK2 is activated upon binding to cyclin E. The cyclin E / CDK2 complex hyperphosphorylates RB to release E2F from Rb and initiates transcription of genes required for the G1 / S transition. Subsequently, CDK2 forms a complex with cyclin A, which regulates S phase progression by activating proteins important for DNA replication and centrosome replication, such as DNA replication permission protein (CDC6) and centrosome protein CP110 (Tadesse et al., Targeting CDK2 in cancer: challenges and opportunities for therapy, Drug Discovery Today. 2019; 25(2):406-413).

[0005] Cyclin E1 is frequently amplified and / or overexpressed in human cancers. In high-grade serous ovarian cancer, cyclin E1 amplification is detected in approximately 20% of patients, and this amplification is associated with chemotherapy resistance / refractory (TCGA, Integrated genomic analyses of ovarian carcinoma, Nature, 2011; 474:609-615; Nakayama et al., Gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer, Cancer, (2010) 116:2621-34). Ovarian cancer cell lines with cyclin E1 amplification are sensitive to agents that inhibit CDK2 activity or reduce cellular CDK2 protein levels, indicating that these cyclin E1 amplified cells are CDK2 dependent (Au-Yeung et al., Selective targeting of cyclin E1 amplified high grade serous ovarian cancer by clin-dependent kinase 2 and AKT inhibition, Clin. Cancer Res. 2017; 23(7):1862-1874).Adverse outcomes and drug resistance are also associated with high cyclin E1 expression in cancers such as endometrial cancer, gastric cancer, and breast cancer (Noske et al., Detection of CCNE1 / URI(19q12) amplification by in situ hybridization is common in high-grade and type II endometrial cancer, Oncotarget (2017) 8:14794-14805; Ooi et al., Gene amplification of CCNE1, CCND1 and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situ). Hybridization [Detection of gene amplification of CCNE1, CCND1 and CDK6 in gastric cancer by multiple linkage-dependent probe amplification and fluorescence in situ hybridization], HumPathol. [Human Pathology] (2017) 61:58-67; Keyomarsi et al., Cyclin E and survival inpatients with breast cancer. [Cyclin E and survival in breast cancer patients] N Engl J Med. [New England Journal of Medicine] (2002) 347:1566-75). Estrogen receptor (ER) positive breast cancer cell lines with acquired resistance to the CDK4 / 6 inhibitor palbociclib exhibit elevated cyclin E1 expression and can be resensitized after CDK2 inhibition (Herrera-Abreu et al., Early adaptation and acquired resistance to CDK4 / 6 inhibition in estrogen receptor-positive breast cancer, Cancer Res. (2016) 76: 2301-2313).It was also reported that in ER+BC, high cyclin E1 levels were associated with poor response to palbociclib plus fulvestrant combination therapy (high CCNE1 vs. low CCNE1: median PFS 7.6 months vs. 14.1 months for the palbociclib + fulvestrant arm; 4.0 months vs. 4.8 months for the placebo + fulvestrant arm), further highlighting the importance of CDK2 activity in mediating resistance to CDK4 / 6 inhibitors (Turner et al., Cyclin E1 expression and Palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer, Clin Oncol. (2019) 37(14):1169-1178).

[0006] It has been reported that cyclin E2 (CCNE2) overexpression is associated with endocrine resistance in breast cancer cells. It has also been reported that CDK2 inhibition can restore sensitivity to tamoxifen and CDK4 inhibitors in tamoxifen-resistant and CCNE2-overexpressing cells. (Caldon et al., Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther. (2012) 11:1488-99; Herrera-Abreu et al., Early Adaptation and Acquired Resistance to CDK4 / 6 Inhibition in Estrogen Receptor-Positive Breast Cancer. Cancer Res. (2016) 76:2301-2313). Furthermore, cyclin E amplification has also been reported to contribute to trastuzumab resistance in HER2+ breast cancer. (Scaltriti et al., Cyclin E amplification / overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients, Proc Natl Acad Sci. (2011) 108:3761-6). Furthermore, cyclin E overexpression has been reported to play a role in basal-like and triple-negative breast cancer (TNBC), as well as inflammatory breast cancer.(Elsawaf & Sinn, Triple Negative Breast Cancer: Clinical and Histological Correlations, Breast Care (2011) 6:273-278; Alexander et al., Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer, Oncotarget (2017) 8:14897-14911.) Summary of the Invention

[0007] The importance of CDK2 in the proliferation pathway and the frequently altered CDK2 / cyclin E1 activity in tumors highlight the role of CDK2 as a therapeutic target for cancer. CDK2 knockout mice are viable with minimal defects, indicating that CDK2 is not essential for normal cell proliferation (Berthet et al., CDK2 knockout mice are viable. Curr Biol. [Modern Biology] (2003) 13(20):1775-85). Furthermore, selective CDK2 inhibitors can minimize clinical toxicity while remaining active in treating patients with high expression of cyclin E1 and / or E2 in tumor cells. However, in some implementations, inhibition of CDK2, as well as other CDKs, may also be clinically beneficial.

[0008] In various embodiments, this disclosure relates to novel heteroaryl compounds that can inhibit CDK2, for example, selectively inhibiting CDK2 relative to other CDKs and / or other kinases. The compounds and compositions described herein can be used to treat a variety of diseases or disorders, such as cancers, including those characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2).

[0009] Some embodiments disclosed herein relate to compounds having formula I or II or pharmaceutically acceptable salts thereof.

[0010]

[0011] These variables are defined herein. In some embodiments, compounds having Formula I may have subformulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB as defined herein. In some embodiments, compounds having formula II may have subformulas II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4 as defined herein. In some embodiments, this disclosure also provides specific compounds selected from any one of Examples 1-155, or any specific compounds disclosed in Tables 1A or 1B herein, or pharmaceutically acceptable salts thereof.

[0012] In some embodiments, this disclosure provides pharmaceutical compositions comprising one or more compounds disclosed herein and optionally pharmaceutically acceptable excipients. The pharmaceutical compositions are generally formulated for oral administration.

[0013] In some embodiments, this disclosure also provides a method for inhibiting CDK activity, such as CDK2 activity, in a subject or biological sample. In some embodiments, the method includes reacting the subject or biological sample with an effective amount of one or more compounds of this disclosure (e.g., compounds having Formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA...). -5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or contact with pharmaceutical compositions containing the thereof.

[0014] In some embodiments, this disclosure provides methods for treating or preventing CDK-mediated diseases or disorders in subjects of need. In some embodiments, the method includes administering to the subject an effective amount of one or more compounds of this disclosure or pharmaceutical compositions herein. In some embodiments, the method includes administering to the subject an effective amount of a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B). IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0015] In some embodiments, this disclosure also provides a method for treating or preventing cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, I...). A-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or an effective amount of the pharmaceutical composition described herein. In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma, or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach cancer (or gastric cancer), thyroid cancer, and combinations thereof. In some embodiments, the cancer is selected from breast cancer of the following types: ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC); and inflammatory breast cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is selected from breast cancer of the following types: endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the cancer is advanced or metastatic breast cancer. In some embodiments, the cancer is ovarian cancer.

[0016] The administration described herein is not limited to any particular route of administration. For example, in some embodiments, the administration may be oral, nasal, percutaneous, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, the administration is oral. In some embodiments, the administration is parenteral injection, such as intravenous injection.

[0017] The compounds disclosed herein can be used as a monotherapy or in combination therapy. In some embodiments of the methods described herein, one or more of the compounds disclosed herein may be administered as the sole or only active ingredient. In some embodiments, the methods herein further include administering additional therapeutic agents to the subject, such as the additional anticancer agents described herein.

[0018] It should be understood that the foregoing description of the invention and the following detailed description are merely exemplary and illustrative, and do not limit the invention herein. Detailed Implementation

[0019] In various embodiments, this disclosure provides compounds and compositions that can be used to inhibit CDKs such as CDK2 and / or to treat or prevent the various diseases or disorders described herein, such as cancer.

[0020] compound

[0021] The compounds disclosed herein are generally aminopyridine or aminopyrimidine derivatives having formula I or II as described herein. The compounds herein generally inhibit CDK2. In some embodiments, the compounds herein selectively inhibit CDK2 relative to other CDKs. For example, as shown in the Examples section herein, certain exemplary compounds have shown to be more effective than CDK1 in inhibiting CDK2, with selectivity exceeding 10-fold and up to about 30-fold or higher.

[0022] Formula I

[0023] In some embodiments, this disclosure provides compounds having Formula I or pharmaceutically acceptable salts thereof:

[0024]

[0025] in:

[0026] L 1 It is an optionally substituted arylene (e.g., phenylene), an optionally substituted heteroarylene (e.g., 5- or 6-membered heteroarylene), an optionally substituted heterocyclic group (e.g., 4-8-membered heterocyclic group), or an optionally substituted carbocyclic group (e.g., C10-C ... 3-8 (subcarbonyl group);

[0027] R 1 It is SO2R 10 SO2NR 11 R 12 S(O)(NH)R 10 、or C(O)NR 11 R 12 ; or R 1 Is it hydrogen or NR? 11 R12 ;

[0028] X is N or CR 13 ;

[0029] L 2 It is a key, -N(R) 14 )-, or -O-;

[0030] L 3 It is a key, the C that is arbitrarily replaced. 1-4 Alkylene or optionally substituted C 1-4 Heteroalkyl;

[0031] R 2 It is hydrogen, with C optionally substituted. 3-8 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted 4-10 membered heterocyclic group, optionally substituted phenyl group, or optionally substituted 5-10 membered heteroaryl group;

[0032] R 3 It is hydrogen, halogens (e.g., F), CN, C(O)NR 11 R 12 C, which is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 alkynyl group, optionally substituted C 1-4 Heteroalkyl, OR A COR B COOR A NR 11 R 12 C, which is arbitrarily replaced 3-8 Carbocyclic group, optionally substituted 4-10-membered heterocyclic group, or optionally substituted 5-10-membered heteroaryl group;

[0033] R 4 It is hydrogen, halogen (e.g., F), or optionally substituted C. 1-6 Alkyl, or NR 11 R 12 ;

[0034] Or L 2 and R 3 Together with the inserted atoms, they form optionally substituted 4-8 membered ring structures; or R 3 and R 4 Together with the inserted atoms, they form optional 4-8 membered ring structures;

[0035] in:

[0036] R 10C is arbitrarily replaced 1-6 Alkyl groups (e.g., C-shaped groups optionally substituted with carbocyclic, heterocyclic, or heteroaryl groups) 1-4 Alkyl groups, optionally substituted C4 groups 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5-membered or 6-membered heteroaryl group), or optionally substituted 4-10-membered heterocyclic group;

[0037] R 11 and R 12 Each of them, each time it appears, is independently hydrogen, optionally substituted C. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl group), optionally substituted 4- to 10-membered heterocyclic group; or nitrogen protecting group; or R 11 and R 12 They can be linked to form optionally substituted 4-10 member heterocyclic groups or 5- or 6-membered heteroaryl groups;

[0038] R A It is hydrogen, with C optionally substituted. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl group), optionally substituted 4- to 10-membered heterocyclic group; or oxygen protecting group;

[0039] R B It is hydrogen, with C optionally substituted. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted 4-10-membered heterocyclic group, or optionally substituted heteroaryl group (e.g., 5-membered or 6-membered heteroaryl group);

[0040] R 13 It is hydrogen, F, CN, -OH, or optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl groups, optionally substituted C 3-8 Carbocyclic group, or optionally substituted 4-10 membered heterocyclic group; and

[0041] R 14 It is hydrogen, with C optionally substituted. 1-6 Alkyl groups, optionally substituted C 3-8 A carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl group), optionally substituted 4- to 10-membered heterocyclic group; or a nitrogen-protecting group.

[0042] In some embodiments, compounds having Formula I (including any applicable sub-formulas described herein) may contain one or more asymmetric centers and / or axial chirality, and thus can exist in a variety of stereoisomeric forms (e.g., enantiomers and / or diastereomers). In some embodiments, compounds having Formula I may exist as individual enantiomers and / or diastereomers (if applicable), or mixtures of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). In some embodiments, when applicable, compounds having Formula I (including any applicable sub-formulas described herein) may exist as individual enantiomers that are substantially free of (e.g., less than 20%, less than 10%, less than 5%, less than 1% by weight, or have undetectable amounts, by HPLC or SFC area or both). In some embodiments, when applicable, compounds having Formula I (including any applicable sub-formulas described herein) may also exist as mixtures of stereoisomers (in any ratio), such as racemic mixtures.

[0043] In some embodiments, compounds having Formula I (including any applicable sub-formulas as described herein) may exist as isotopically labeled compounds, particularly deuterated analogs, wherein one or more hydrogen atoms of the compound having Formula I are replaced by deuterium atoms with an abundance higher than their native abundance, for example, CD3 analogs when the compound has a CH3 group.

[0044] It will be apparent to those skilled in the art that, in certain circumstances, compounds having Formula I can exist as mixtures of tautomers. This disclosure is not limited to any particular tautomer. Rather, this disclosure covers any and all such tautomers, whether or not explicitly drawn or mentioned.

[0045] Typically, X in Formula I is N, and a compound having Formula I can be characterized as having Formula IA:

[0046]

[0047] Where L 1 L 2 L 3 R 1 R 2 R 3 and R 4 This includes any of those described herein in any combination.

[0048] In some implementations, X in Equation I may be CR 13 , where R 13 Defined herein. For example, in some implementations, R 13It can be hydrogen, and compounds having formula I can be characterized as having formula IB:

[0049]

[0050] Where L 1 L 2 L 3 R 1 R 2 R 3 and R 4 This includes any of those described herein in any combination.

[0051] Multiple groups are suitable as L in Formula I 1 For example, in some implementations, L in Formula I 1 It can be an optionally substituted phenylene. In some embodiments, L in Formula I... 1 It can be an optionally substituted 5- or 6-membered heteroaryl group, such as those having 1-3 independently selected cyclic heteroatoms chosen from N, O, and S. In some embodiments, L in Formula I... 1 It can be an optionally substituted 4-8 membered subheterocyclic group, such as a monocyclic or bicyclic (e.g., fused, bridged, or spirobicyclic) 4-8 membered subheterocyclic group having 1-2 independently selected cyclic heteroatoms from N, O, and S. In some embodiments, L in Formula I... 1 C can be arbitrarily replaced 3-8 Subcarbonyl groups, such as monocyclic or bicyclic (e.g., fused, bridged, or spirobicyclic) subcarbonyl groups.

[0052] In some specific implementations, L in formula I (e.g., any sub-formula described herein, such as formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB, if applicable) 1 Selected from:

[0053]

[0054] in:

[0055] When valence is allowed, n is 0, 1, 2, 3, or 4; and

[0056] R 100 Each time it appears, it is independently selected from halogens (e.g., F or Cl), CN, OH, or optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Alkoxy groups, and optionally substituted C groups 1-4Heteroalkyl. Typically, n is 0, 1, or 2.

[0057] In some embodiments, L in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It is an unsubstituted phenylene, pyridylene, piperidinylene, or cyclohexylene. For example, in some embodiments, L 1 yes:

[0058]

[0059] In some specific embodiments, L in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 Selected from:

[0060]

[0061] in:

[0062] n is 1 or 2; and

[0063] R 100 Each time it appears, it is independently selected from F, Cl, CN, OH, or C that is optionally substituted by F. 1-4 Alkyl groups, C groups optionally substituted with F 1-4 Alkoxy groups, and C groups optionally substituted with F. 1-4 Heteroalkyl groups.

[0064] In some embodiments, L in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It is phenylene, pyridinyl, piperidinyl, or cyclohexylene, each of which may optionally be further substituted, for example, monosubstituted or disubstituted. For example, in some embodiments, L in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 Selected from:

[0065]

[0066] in:

[0067] R 100 It is F, Cl, CN, OH, methyl, fluorine-substituted methyl (e.g., CF3), methoxy, or fluorine-substituted methoxy. In any embodiment herein, unless otherwise stated or contrary to the context, L in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 You can choose from: In any implementation herein, unless otherwise stated or contrary to the context, L in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be

[0068] R in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 The group is typically a sulfone, sulfonamide, sulfonamide, or amide. For example, in some embodiments, R in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be SO2R 10 , where R 10 Defined herein. In some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be SO2NR 11 R 12 , where R 11 and R 12Defined herein. In some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be S(O)(NH)R 10 , where R 10 Defined herein. In some implementations, R in Formula I (e.g., Formula IA or IB) 1 It could be C(O)NR 11 R 12 , where R 11 and R 12 Defined in this article.

[0069] In some more specific embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be SO2R 10 , where R 10 C is arbitrarily replaced 1-4 Alkyl groups, optionally substituted C 3-6 Cycloalkyl groups, or optionally substituted 4-8 membered heterocyclic groups having one or two independently selected cyclic heteroatoms chosen from N, O, and S. In some more specific embodiments, R in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be SO2R 10 , where R 10 It is a 5- or 6-membered heteroaryl group having 1 to 3 independently selected cyclic heteroatoms chosen from N, O and S, which are optionally substituted.

[0070] In some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be SO2R 10 , where R 10 It is C 1-4 Alkyl, (C 1-4 Alkylene) j -C 3-6cycloalkyl, or (C 1-4 Alkylene) j - A 4-8 member monocyclic heterocyclic group having one or two independent cyclic heteroatoms selected from N, O, and S, or R 10 Yes (C) 1-4 Alkylene) j -(5- or 6-membered heteroaryl groups having 1-3 independent cyclic heteroatoms selected from N, O, and S),

[0071] Where j is 0 or 1, and the C 1-4 The alkylene group is a straight-chain or branched alkylene chain optionally substituted with F; and

[0072] Among them, C 1-4 Alkyl, C 3-6 Each of the cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 8-membered monocyclic heterocyclic groups is optionally selected independently by one or more (e.g., 1, 2, or 3) oxo, F, G 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, R 10 C is a C that can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups, such as CH2F, CF3, etc. In some embodiments, R 10 Yes – (C 1-4 (alkylene)-C 3-6 Cycloalkyl groups, such as CH2-cyclopropyl, may optionally be substituted. In some embodiments, R 10 Yes – (C 1-4 (alkylene)-(4-8 membered monocyclic heterocyclic group), such as –CH2-tetrahydrofuranyl, which may optionally be substituted. In some embodiments, R 10 It can be a 5- or 6-membered heteroaryl group having 1-3 independent cyclic heteroatoms selected from N, O, and S, such as pyrazole, imidazole, triazole, etc., which can be optionally substituted, for example, by C. 1-4Alkyl (e.g., methyl) substitution. In any embodiment herein, unless otherwise stated or contrary to the context, R in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be SO2Me. In some implementations, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 You can choose from: In some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 You can choose from: In some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 You can choose from:

[0073]

[0074] In some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be S(O)(NH)R 10 ,Right now Where R 10 C is arbitrarily replaced 1-4 Alkyl groups, optionally substituted C 3-6 Cycloalkyl, or a 4-8 membered heterocyclic group having one or two independently selected cyclic heteroatoms chosen from N, O and S, or a 5- or 6-membered heteroaryl group having one to three independently selected cyclic heteroatoms chosen from N, O and S, that are optionally substituted.

[0075] In some more specific embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be S(O)(NH)R 10 ,Right now Where R 10 It is C 1-4 Alkyl, (C 1-4 Alkylene) j -C 3-6 cycloalkyl, (C 1-4 Alkylene) j - A 4-8 member monocyclic heterocyclic group having one or two independent cyclic heteroatoms selected from N, O, and S, or R 10 Yes (C) 1-4 Alkylene) j -(5- or 6-membered heteroaryl groups having 1-3 independent cyclic heteroatoms selected from N, O, and S),

[0076] Where j is 0 or 1, and the C 1-4 The alkylene group is a straight-chain or branched alkylene chain optionally substituted with F; and

[0077] Among them, C 1-4 Alkyl, C 3-6 Each of the cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 8-membered monocyclic heterocyclic groups is optionally selected independently by one or more (e.g., 1, 2, or 3) oxo, F, G 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some embodiments, j is 0. In some embodiments, j is 1. In any embodiment herein, unless otherwise stated or contrary to the context, R in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1It can be S(O)(NH)Me.

[0078] In some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be SO2NR 11 R 12 , where R 11 and R 12 Independently hydrogen, optionally substituted C 1-4 Alkyl groups, optionally substituted C 3-6 Cycloalkyl groups, or optionally substituted 4-8 membered heterocyclic groups having one or two independently selected cyclic heteroatoms chosen from N, O, and S. In some embodiments, R 11 and R 12 One of them is hydrogen, and R 11 and R 12 Another one is described herein. For example, in some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be SO2NR 11 R 12 , where R 11 and R 12 One of them is hydrogen, and R 11 and R 12 The other is hydrogen, with C optionally substituted. 1-4 Alkyl groups, optionally substituted C 3-6 Cycloalkyl groups, or optionally substituted 4- to 8-membered heterocyclic groups having one or two independently selected cyclic heteroatoms chosen from N, O, and S.

[0079] In some more specific embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be SO2NR 11 R 12 , where R 11 and R 12 Independently, it is hydrogen and C 1-4 Alkyl, (C 1-4 Alkylene) j -C3-6 cycloalkyl, (C 1-4 Alkylene) j - A 4-8 member monocyclic heterocyclic group having one or two independent cyclic heteroatoms selected from N, O, and S.

[0080] Where j is 0 or 1, and the C 1-4 The alkylene group is a straight-chain or branched alkylene chain optionally substituted with F; and

[0081] Among them, C 1-4 Alkyl, C 3-6 Each of the cycloalkyl and 4-8 membered monocyclic heterocyclic groups is optionally selected independently by one or more (e.g., 1, 2, or 3) oxo, deuterium, F, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, R 11 and R 12 One of them is hydrogen, and R 11 and R 12 Another one is described herein. In some implementations, R 11 and R 12 One of them is methyl or CD3, and R 11 and R 12 Another one is described herein. In some implementations, R 11 and R 12 Both are hydrogen. In some embodiments, R 11 and R 12 One of them is hydrogen, and R 11 and R 12 Another is C, which is optionally replaced by 1-3 F and / or deuterium. 1-4 Alkyl groups, such as CH3, isopropyl, tert-butyl, CD3, etc. In some embodiments, R... 11 and R 12 One of them is hydrogen, and R 11 and R 12 The other one is C.3-6 The cycloalkyl group, for example, cyclopropyl or cyclobutyl, may optionally be substituted, for example, substituted with one or both F. In some embodiments, R 11 and R 12 One of them is hydrogen, and R 11 and R 12 Another type is a 4-8 membered monocyclic heterocyclic group having 1-3 independent cyclic heteroatoms selected from N, O, and S, such as oxetane, tetrahydrofuran, tetrahydropyran, piperidine, etc., which can be optionally substituted, for example by C. 1-4 Alkyl (e.g., methyl) substitution. In some embodiments, R 11 and R 12 One of them is hydrogen, and R 11 and R 12 Another one is –(C) 1-4 Alkylene group (4-8 membered monocyclic heterocyclic group having 1-3 independent cyclic heteroatoms selected from N, O and S), such as -CH2- (oxetane), etc., which may optionally be substituted, for example by C 1-4 Alkyl (e.g., methyl) substitution.

[0082] In some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be SO2NR 11 R 12 , where R 11 and R 12 Linked to form optionally substituted 4-8 membered heterocyclic groups, except R 11 and R 12 In addition to the attached nitrogen atom, the 4-8 membered heterocyclic group also has 0 or 1 cyclic heteroatom selected from N, O, and S. For example, in some embodiments, R in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be SO2NR 11 R 12 , where R 11 and R 12 Linked to form 4-8 member monocyclic heterocyclic groups, except R 11 and R 12In addition to the attached nitrogen atom, the 4-8 membered monocyclic heterocyclic group also has 0 or 1 cyclic heteroatom selected from N, O, and S, such as morpholino or piperazine, which is optionally independently selected by one or more (e.g., 1, 2, or 3) oxo, deuterium, F, G 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

[0083] In some preferred embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be SO2 or NH2. In some preferred embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 You can choose from:

[0084] In some preferred embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 You can choose from:

[0085] In some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be C(O)NR 11 R 12 , where R 11 and R12 Independently hydrogen, with C optionally substituted. 1-4 Alkyl groups, optionally substituted C 3-6 Cycloalkyl, or optionally substituted 4-8 membered heterocyclic groups having one or two independently selected cyclic heteroatoms chosen from N, O, and S. In some embodiments, R 11 and R 12 One of them is hydrogen, and R 11 and R 12 Another one is described herein. For example, in some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be C(O)NR 11 R 12 , where R 11 and R 12 One of them is hydrogen, and R 11 and R 12 The other is hydrogen, which is optionally replaced by C. 1-4 Alkyl groups, optionally substituted C 3-6 Cycloalkyl, or a 4- to 8-membered heterocyclic group having one or two independently substituted cyclic heteroatoms selected from N, O, and S.

[0086] For example, in some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be C(O)NR 11 R 12 , where R 11 and R 12 Independently, it is hydrogen, C 1-4 Alkyl, (C 1-4 Alkylene) j -C 3-6 cycloalkyl, (C 1-4 Alkylene) j - A 4-8 member monocyclic heterocyclic group having one or two independent cyclic heteroatoms selected from N, O, and S.

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

[0088] Among them, C 1-4 Alkyl, C 3-6Each of the cycloalkyl and 4-8 membered monocyclic heterocyclic groups is optionally selected independently by one or more (e.g., 1, 2, or 3) oxo, deuterium, F, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, R 11 and R 12 One of them is hydrogen, and R 11 and R 12 Another one is described herein. For example, in some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be C(O)NHMe.

[0089] In some embodiments, R in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be C(O)NR 11 R 12 , where R 11 and R 12 Linked to form optionally substituted 4-8 membered heterocyclic groups, except R 11 and R 12 In addition to the attached nitrogen atom, the 4-8 membered heterocyclic group also has 0 or 1 cyclic heteroatom selected from N, O, and S. For example, in some embodiments, R in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It could be C(O)NR 11 R12 , where R 11 and R 12 Linked to form 4-8 member monocyclic heterocyclic groups, except R 11 and R 12 In addition to the attached nitrogen atom, the 4-8 membered monocyclic heterocyclic group also has 0 or 1 cyclic heteroatom selected from N, O, and S, which is optionally selected independently by one or more (e.g., 1, 2, or 3) oxo, deuterium, F, and G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. For example, in some embodiments, R in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 It can be

[0090] Compounds having formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) may have L 1 and R 1 Various combinations thereof are used, which are not particularly limiting of this disclosure. In any embodiment herein, unless otherwise stated or contrary to the context, L in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 -R 1 You can choose from:

[0091] Or L 1 -R 1 yes

[0092] In any implementation herein, unless otherwise stated or contrary to the context, L in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 -R 1 You can choose from:

[0093]

[0094] In any implementation herein, unless otherwise stated or contrary to the context, L in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, or IB) 1 -R 1 You can choose from:

[0095] In some implementations, L in Formula I 1 -R 1 It can be In some implementations, L in Formula I 1 -R 1 It can be

[0096] In some preferred embodiments, L in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, or IB) 1 -R 1 Selected from:

[0097]

[0098] In some preferred embodiments, if applicable, L in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB) 1 -R 1It may contain a piperidine ring, for example

[0099]

[0100] For example, in some embodiments, a compound having formula IA can be characterized as having a formula according to any of the following: IA-1, IA-2, IA-3, or IA-4.

[0101]

[0102] Where L 2 L 3 R 2 R 3 and R 4 This includes any of those described herein in any combination.

[0103] In some implementations, L in Formula I (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB) 2 It can be a key, in which case, L 3 -R 2 Directly attached to the pyridine or pyrimidine ring in Formula I.

[0104] In some implementations, L in Formula I (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB) 2 It can be –O-.

[0105] In some embodiments, L in formula I (e.g., formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB) 2 It can be -N(R) 14 )-, where R 14 Defined herein. For example, in some implementations, R 14 It can be hydrogen. In some embodiments, R14 It can be optionally oxidized by oxygen, F, CN, or G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 ) replaced by C 1-4 Alkyl, wherein G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

[0106] In some implementations, L in Formula I (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB) 3 It can be a key, in which case R 2 Directly attached to L 2 , or if L 2 If it is also a key, then R 2 Directly attached to the pyridine or pyrimidine ring in Formula I.

[0107] In some implementations, L in Formula I (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB) 3 C can be arbitrarily replaced 1-4 Alkylene, such as CH2.

[0108] In some implementations, L in Formula I (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB) 3 C can be arbitrarily replaced 1-4 Heteroalkyl groups, such as those described herein.

[0109] Various groups are suitable for use as R in Formula I. 2 For example, in some implementations, R 2 It can be hydrogen. In some embodiments, R 2 C can be arbitrarily replaced 3-8 Alkyl group. In some embodiments, R 2 C can be arbitrarily replaced 3-8 Carbocyclic group. In some embodiments, R 2 It can be an optionally substituted 4-10 membered heterocyclic group, such as a monocyclic or bicyclic (e.g., fused, bridged, or spirobicyclic) heterocyclic group having one or two independent cyclic heteroatoms selected from N, O, and S. In some embodiments, R 2 It can be an optionally substituted phenyl group. In some embodiments, R 2 It can be a 5-10 membered heteroaryl group that is optionally substituted, such as a 5- or 6-membered heteroaryl group having 1-3 independently selected cyclic heteroatoms from N, O and S.

[0110] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R 2 It can be independently selected from one or more (e.g., 1, 2, or 3) oxidases, F, G. 1 CN, OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The substituents of C are substituted with substituents. 3-8 cycloalkyl, wherein G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6Cycloalkyl. In any embodiment herein, unless otherwise stated or contrary to the context, R in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB) 2 You can choose from:

[0111]

[0112] In any embodiment herein, unless otherwise stated or contrary to the context, in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 You can choose from:

[0113]

[0114] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R 2 It can be optionally selected independently from F, CN, G by one or more (e.g., 1, 2, or 3). 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 The substituents of C are substituted with substituents. 3-8 cycloalkyl, wherein G 1Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

[0115] In some preferred embodiments, in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, are optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from F, methyl, ethyl, hydroxyethyl (e.g., -CH2CH2OH or -CH(OH)CH3), -C(O)CH3, OH, -CH2OH, fluorinated methyl (e.g., -CF2H), and fluorinated ethyl (e.g., -CH2CF2H). In some embodiments, R in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB) 2 It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, are substituted with one or two substituents independently selected from OH, -CH2CH2OH, -CH(OH)CH3), -CH2OH, -CF2H, and -CH2CF2H, and optionally further substituted with F, methyl, or ethyl.

[0116] In some preferred embodiments, in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2Is it a spiral, fused, or bridged C? 6-8 cycloalkyl, for example It is optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from F, methyl, ethyl, hydroxyethyl (e.g., -CH2CH2OH or -CH(OH)CH3), -C(O)CH3, OH, -CH2OH, fluorinated methyl (e.g., -CF2H), and fluorinated ethyl (e.g., -CH2CF2H). In some embodiments, R in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB) 2 Is it a spiral, fused, or bridged C? 6-8 cycloalkyl, for example It is substituted by one or two independent substituents selected from OH, -CH2CH2OH, -CH(OH)CH3), -CH2OH, -CF2H, and -CH2CF2H, and optionally further substituted by F, methyl, or ethyl.

[0117] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R 2 It can be a 4-10 membered heterocyclic group having 1-4 independently selected cyclic heteroatoms chosen from N, O, and S, optionally with one or more (e.g., 1, 2, or 3) independently selected from oxo, 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(G1 (G) 2 ), C(O)-NH(G 2 ), and C(O)-N(G 1 (G) 2 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The substituents of the 4-10 member heterocyclic group are substituted; and the two substituents of the heterocyclic group, together with one or more inserted atoms, may optionally be linked to form a fused, bridged or spirocyclic structure.

[0118] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R 2 It is a 4-8 membered heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S, which are optionally selected by one or more (e.g., 1, 2, or 3) independently selected from oxo, 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 Substituents of ) where G1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

[0119] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R 2 It can be a 4-8 membered monocyclic, saturated, or partially unsaturated heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S, such as pyrrolidine, piperidine, azepane, etc., optionally having one or more (e.g., 1, 2, or 3) independently selected from oxo, 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 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The substituents of the 4-8 membered heterocyclic group are substituted; and the two substituents of the 4-8 membered heterocyclic group, together with one or more inserted atoms, may optionally be linked to form a fused, bridged or spirocyclic structure.

[0120] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R 2 It can be a 4-6 or 7-membered monocyclic heterocyclic group having 1-2 independently selected cyclic heteroatoms from N, O and S, such as oxepane, azacyclobutane, tetrahydrofuran, tetrahydropyran, oxepane, pyrrolidine, piperidine, etc., optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from oxo, F, methyl, ethyl, hydroxyethyl (e.g., -CH2CH2OH or -CH(OH)CH3), -C(O)CH3, OH, -CH2OH, fluorinated methyl (e.g., -CF2H), and fluorinated ethyl (e.g., -CH2CF2H). In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R 2 It can be a 4-6 or 7-membered monocyclic heterocyclic group having 1-2 independently selected cyclic heteroatoms from N, O and S, such as oxetane, azirone, tetrahydrofuran, tetrahydropyran, oxetane, pyrrolidine, piperidine, etc., which is substituted by one or two independently selected substituents from OH, -CH2CH2OH, -CH(OH)CH3), -CH2OH, -CF2H and -CH2CF2H, and optionally further substituted by F, methyl or ethyl.

[0121] In some embodiments, R is 2 You can choose from:

[0122]

[0123] in:

[0124] m is 0, 1, 2, 3 or 4;

[0125] R 101 Each time it appears, it is independently of oxygen, F, CN, G. 1 G 2 OH, OG 1 and OG 2 G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears, it is independently a 4-6 membered heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S, a phenyl group, or a 5- or 6-membered heteroaryl group having 1-4 cyclic heteroatoms independently selected from N, O, and S, each of which is optionally composed of 1-3 cyclic heteroatoms independently selected from F, CN, G. 1 OH and OG 1 Substituents; where two R groups are substituents; 101 Together with one or more inserted atoms, they can optionally be linked to form fused, bridged, or spirocyclic structures. In some embodiments, m can be 0, 1, 2, or 3. For example, in some embodiments, m is 0, i.e., the heterocyclic group is not substituted. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R 101 Each time it appears, it is independently F, OH, CN, C. 1-4 Alkyl (e.g., methyl, ethyl, propyl, etc.), phenyl, cyclopropyl, hydroxymethyl (-CH2OH), methoxy, fluorinated methoxy, fluorinated C 1-4Alkyl groups (e.g., fluorinated methyl groups, such as CF2H, or fluorinated ethyl groups, such as CH2CF2H)).

[0126] In some preferred embodiments, in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 You can choose from:

[0127]

[0128] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R 2 It can also be optionally selected independently from F, CN, G by one or more (e.g., 1, 2, or 3). 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 ) of the substituents of the phenyl group, wherein G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C.1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The phenyl group is substituted with a substituent; wherein two optional substituents of the phenyl group, together with one or more inserted atoms, may optionally be linked to form a fused ring structure.

[0129] For example, in some embodiments, in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 It can be

[0130]

[0131] in:

[0132] m is 0, 1, 2, or 3;

[0133] R 101 Each time it appears, it is independently F, CN, G. 1 G 2 OH, OG 1 OG 2 NH2, NH(G) 1 ), NH(G 2 ), N(G 1 (G) 1 ), and N(G 1 (G) 2 ), where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2Each time it appears, it is independently a 4-6 membered heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S, a phenyl group, or a 5- or 6-membered heteroaryl group having 1-4 cyclic heteroatoms independently selected from N, O, and S, each of which is optionally composed of 1-3 cyclic heteroatoms independently selected from F, CN, G. 1 OH and OG 1 Substituents; where two R groups are substituents; 101 Together with one or more inserted atoms, they can optionally be linked to form a fused ring structure. In some embodiments, m can be 0, 1, 2, or 3. For example, in some embodiments, m is 0, i.e., the phenyl group is unsubstituted. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, R 101 Each time it appears, it is independently F, OH, CN, C. 1-4 Alkyl (e.g., methyl, ethyl, propyl, etc.), cyclopropyl, cyclobutyl, oxetane, C 1-4 Alkyl groups (e.g., methoxy groups), fluorine-substituted C groups 1-4 Alkoxy groups (e.g., fluorinated methoxy groups), fluorinated C 1-4 Alkyl groups (e.g., fluorinated methyl groups, such as CF2H, or fluorinated ethyl groups, such as CH2CF2H). In some preferred embodiments, R 101 Each time it appears, it is independently F or C. 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, etc.), OH, cyclopropyl, cyclobutyl, oxetyl, or CN.

[0134] In some preferred embodiments, in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 You can choose from:

[0135]

[0136] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R2 It can also be a 5-10 membered heteroaryl group having 1-4 independently selected cyclic heteroatoms chosen from N, O, and S, optionally by one or more (e.g., 1, 2, or 3) independently selected from 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 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The heteroaryl group is substituted with a substituent; and the two optional substituents of the heteroaryl group, together with one or more inserted atoms, may optionally be linked to form a fused ring structure.

[0137] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R 2 It can be a 5- or 6-membered heteroaryl group having 1 to 4 cyclic heteroatoms independently selected from N, O, and S, such as pyridinyl (e.g., 2-, 3-, or 4-pyridinyl), pyrazole, etc., which is optionally independently selected by one or more (e.g., 1, 2, or 3) cyclic heteroatoms from 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 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1The substituents of the heteroaryl group are substituted; and the two optional substituents of the heteroaryl group, together with one or more inserted atoms, may optionally be linked to form a fused ring structure. In any embodiment herein, unless otherwise stated or contrary to the context, in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 You can choose from:

[0138]

[0139] In some embodiments, in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6 R 2 It can be an 8-10 membered bicyclic heteroaryl group having 1-4 cyclic heteroatoms independently selected from N, O, and S, such as indole, indazole, etc., which is optionally composed of one or more (e.g., 1, 2, or 3) independently selected from 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 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The heteroaryl group is substituted with a substituent; and the two optional substituents of the heteroaryl group, together with one or more inserted atoms, may optionally be linked to form a fused ring structure.

[0140] In any embodiment herein, unless otherwise stated or contrary to the context, in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 You can choose from:

[0141]

[0142] In any embodiment herein, unless otherwise stated or contrary to the context, in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 You can choose from:

[0143]

[0144] In any embodiment herein, unless otherwise stated or contrary to the context, in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 You can choose from:

[0145]

[0146] In any embodiment herein, unless otherwise stated or contrary to the context, in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 You can choose from:

[0147]

[0148] In any embodiment herein, unless otherwise stated or contrary to the context, in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 You can choose from:

[0149]

[0150] In any embodiment herein, unless otherwise stated or contrary to the context, in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, 1A, 1A-1, 1A-2, 1A-3, 1A-4, 1A-5A, 1A-6A, 1A-7A, 1A-8A, 1A-9A, 1A-10A, 1A-5B, 1A-6B, 1A-7B, 1A-8B, 1A-9B, 1A-10B, or IB), R 2 You can choose from:

[0151]

[0152] In formula I, R 2 L 2 and L 3 The combination is not particularly limited. For example, in some embodiments, in formula I (e.g., formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), L 2 It can be -O- and L 3 C may be a bond or optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from F, OH, and protected OH. 1-4 Alkylene (e.g., CH2). For example, in some embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-1 or I-2:

[0153]

[0154] Where L 1 R 1 R 2 R 3 and R 4 This includes any of those described herein in any combination.

[0155] In some implementations, in formula I (e.g., formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), L 2 It can be –N(R) 14 )-, where R 14 Defined in this document, and L 3 C may be a bond or optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from F, OH, and protected OH. 1-4Alkylene (e.g., CH2). For example, in some embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-3 or I-4:

[0156]

[0157] Where L 1 R 1 R 2 R 3 R 4 and R 14 This includes any of those described herein in any combination. Typically, R in Equation I-3 or I-4... 14 Is it hydrogen or C? 1-4 Alkyl (e.g., methyl).

[0158] In some preferred embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-1, I-2, I-3, or I-4, wherein R 2 It is independently selected from one or more (e.g., 1, 2, or 3) oxidases, F, G. 1 CN, OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The substituents of C are substituted with substituents. 3-8 Alkyl, wherein G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein the C 3-8 Two optional substituents of the alkyl group, together with one or more inserted atoms, may optionally be linked to form a ring structure, such as spiro-C. 3-6 Cycloalkyl or 4-7 membered heterocyclic groups. In any embodiment herein, unless otherwise stated or contrary to context, R in formula I-1, I-2, I-3, or I-4 2 You can choose from the following:

[0159]

[0160] In any implementation herein, unless otherwise stated or contrary to the context, in formulas I-1, I-2, I-3, or I-4, R 2 You can choose from the following:

[0161]

[0162] In some preferred embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-1, I-2, I-3, or I-4, wherein R 2 It can be optionally selected independently from F, CN, G by one or more (e.g., 1, 2, or 3). 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 The substituents of C are substituted with substituents. 3-8 cycloalkyl, wherein G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some embodiments, R in formula I-1, I-2, I-3 or I-4 2 It can be C 3-6 The cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, is optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from F, methyl, ethyl, hydroxyethyl (e.g., -CH2CH2OH or -CH(OH)CH3), -C(O)CH3, OH, -CH2OH, fluorinated methyl (e.g., -CF2H), and fluorinated ethyl (e.g., -CH2CF2H). In some embodiments, in formula I-1, I-2, I-3, or I-4, R 2 It can be spiral, fused, or bridged C. 6-8cycloalkyl, for example It is optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from F, methyl, ethyl, hydroxyethyl (e.g., -CH2CH2OH or -CH(OH)CH3), -C(O)CH3, OH, -CH2OH, fluorinated methyl (e.g., -CF2H), and fluorinated ethyl (e.g., -CH2CF2H). For example, in any embodiment herein, unless otherwise stated or contrary to the context, in formula I-1, I-2, I-3, or I-4, R 2 You can choose from the following:

[0163]

[0164] In any implementation herein, unless otherwise stated or contrary to the context, in formulas I-1, I-2, I-3, or I-4, R 2 You can choose from the following:

[0165]

[0166] In any implementation herein, unless otherwise stated or contrary to the context, in formulas I-1, I-2, I-3, or I-4, R 2 You can choose from the following:

[0167]

[0168] In any implementation herein, unless otherwise stated or contrary to the context, in formulas I-1, I-2, I-3, or I-4, R 2 You can choose from the following:

[0169]

[0170] In any implementation herein, unless otherwise stated or contrary to the context, in formulas I-1, I-2, I-3, or I-4, R 2 You can choose from the following:

[0171]

[0172] In some preferred embodiments, in formula I-1, I-2, I-3 or I-4, R 2 You can choose from the following:

[0173]

[0174] In some preferred embodiments, in formula I-1, I-2, I-3 or I-4, R 2 You can choose from the following:

[0175]

[0176] In some preferred embodiments, in formula I-1, I-2, I-3 or I-4, R 2 You can choose from the following:

[0177]

[0178]

[0179] As shown in the Examples section, compounds having formulas I-1, I-2, I-3, or I-4 have been found to be effective CDK2 inhibitors, with some examples exhibiting selectivity more than 10-fold higher than CDK1. In particular, the representative compound, Example 9, shows selectivity more than 30-fold higher than CDK1. Other compounds with selectivity more than 10-fold higher than CDK1 are also shown in the examples herein.

[0180] In some embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-2-1:

[0181]

[0182] Where L 1 R 1 R 3 and R 4 This includes any of those described herein in any combination. In some embodiments, compounds having formula I-2-1 may be characterized as having formula I-2-1-S1, I-2-1-S2, I-2-1-S3, or I-2-1-S4:

[0183]

[0184]

[0185] In some embodiments, a compound having any one of the formulas I-2-1-S1, I-2-1-S2, I-2-1-S3, and I-2-1-S4 may exist as a substantially pure stereoisomer, for example, substantially free of (e.g., less than 10%, less than 5%, less than 1% by weight or by HPLC or SFC area, or having an undetectable amount) other potential stereoisomers. For example, in some embodiments, a compound having the formula I-2-1-S1 may be a substantially pure stereoisomer, wherein, among the four possible stereoisomers, the combined amount of the corresponding stereoisomers having the formulas I-2-1-S2, I-2-1-S3, and I-2-1-S4 that may exist, by weight or by HPLC or SFC area, is less than 10%, less than 5%, less than 1%, or has an undetectable amount. In some embodiments, the compound having formula I-2-1 may also be present as a mixture of any two or more of the corresponding formulas I-2-1-S1, I-2-1-S2, I-2-1-S3, and I-2-1-S4 (in any ratio).

[0186] In some preferred embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-1, I-2, I-3, or I-4, wherein R 2 It is a 4-8 membered heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S, which are optionally selected by one or more (e.g., 1, 2, or 3) independently selected from oxo, 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 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some embodiments, R in formula I-1, I-2, I-3 or I-42 It is a 4-6 monocyclic heterocyclic group having 1-2 independently selected cyclic heteroatoms chosen from N, O, and S, such as oxetane, azirone, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, etc., optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from oxo, F, methyl, ethyl, hydroxyethyl (e.g., -CH2CH2OH or -CH(OH)CH3), -C(O)CH3, OH, -CH2OH, fluorinated methyl (e.g., -CF2H), and fluorinated ethyl (e.g., -CH2CF2H). For example, in some embodiments, in formula I-1, I-2, I-3, or I-4, R 2 Can be selected

[0187]

[0188] In some preferred embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-1, I-2, I-3, or I-4, wherein R 2 It can also be a 5- or 6-membered heteroaryl group having 1 to 4 cyclic heteroatoms independently selected from N, O, and S, such as pyridinyl (e.g., 2-, 3-, or 4-pyridinyl), pyrazole, etc., which is optionally independently selected by one or more (e.g., 1, 2, or 3) cyclic heteroatoms from 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 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The substituents of the heteroaryl group are substituted; and the two optional substituents of the heteroaryl group, together with one or more inserted atoms, may optionally be linked to form a fused ring structure. For example, in some embodiments, in formula I-1, I-2, I-3 or I-4, R 2 You can also select from

[0189] In some implementations, in formula I (e.g., formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), L 2 and L 3 Both are keys; in this case, R 2 Directly attached to the pyridine or pyrimidine ring of Formula I. For example, in some embodiments, compounds having Formula I (e.g., Formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having Formula I-5:

[0190]

[0191] Where L 1 R 1 R 2 R 3 and R 4 This includes any of those described herein in any combination.

[0192] In some embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-5, wherein R 2 It can be a 4-10 membered heterocyclic group having 1-4 independently selected cyclic heteroatoms chosen from N, O, and S, optionally with one or more (e.g., 1, 2, or 3) independently selected from oxo, 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 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The substituents of the 4-10 member heterocyclic group are substituted; and the two optional substituents of the 4-10 member heterocyclic group, together with one or more inserted atoms, may optionally be linked to form a fused, bridged or spirocyclic structure.

[0193] In some preferred embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-5, wherein R 2 It is a 4-8 membered monocyclic, saturated, or partially unsaturated heterocyclic group having 1-2 independently selected cyclic heteroatoms from N, O, and S, such as pyrrolidine, piperidine, azepane, etc., optionally having one or more (e.g., 1, 2, or 3) independently selected from oxo, 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 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1The substituents of the 4-8 membered heterocyclic group are substituted; and the two optional substituents of the 4-8 membered heterocyclic group, together with one or more inserted atoms, may optionally be linked to form a fused, bridged or spirocyclic structure.

[0194] In some preferred embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-5, wherein R 2 Can be selected

[0195]

[0196] in:

[0197] m is 0, 1, 2, 3 or 4;

[0198] R 101 Each time it appears, it is independently of oxygen, F, CN, G. 1 G 2 OH, OG 1 and OG 2 G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears, it is independently a 4-6 membered heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S, a phenyl group, or a 5- or 6-membered heteroaryl group having 1-4 cyclic heteroatoms independently selected from N, O, and S, each of which is optionally composed of 1-3 cyclic heteroatoms independently selected from F, CN, G. 1 OH and OG 1 Substituents; where two R groups are substituents; 101 Together with one or more inserted atoms, they can optionally be linked to form fused, bridged, or spirocyclic structures. In some embodiments, m can be 0, 1, 2, or 3. For example, in some embodiments, m is 0, i.e., the heterocyclic group is not substituted. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R 101 Each time it appears, it is independently F, OH, CN, C. 1-4 Alkyl (e.g., methyl, ethyl, propyl, etc.), phenyl, cyclopropyl, hydroxymethyl (-CH2OH), methoxy, fluorinated methoxy, fluorinated C1-4 Alkyl groups (e.g., fluorinated methyl groups, such as CF2H, or fluorinated ethyl groups, such as CH2CF2H).

[0199] In any implementation thereof, unless otherwise stated or contrary to the context, in Equation I-5, R 2 You can choose from:

[0200]

[0201] In some embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-5, wherein R 2 It can be optionally selected independently from F, CN, G by one or more (e.g., 1, 2, or 3). 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 ) of the substituents of the phenyl group, wherein G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1NH2, NH(G) 1 ), and N(G 1 (G) 1 The phenyl group is substituted with a substituent; wherein two optional substituents of the phenyl group, together with one or more inserted atoms, may optionally be linked to form a fused ring structure.

[0202] For example, in some preferred embodiments, in formula I-5, R 2 It can be

[0203]

[0204] in:

[0205] m is 0, 1, 2, or 3;

[0206] R 101 Each time it appears, it is independently F, CN, G. 1 G 2 OH, OG 1 OG 2 NH2, NH(G) 1 ), NH(G 2 ), N(G 1 (G) 1 ), and N(G 1 (G) 2 ), where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears, it is independently a 4-6 membered heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S, a phenyl group, or a 5- or 6-membered heteroaryl group having 1-4 cyclic heteroatoms independently selected from N, O, and S, each of which is optionally composed of 1-3 cyclic heteroatoms independently selected from F, CN, G. 1 OH and OG 1 Substituents; where two R groups are substituents; 101 Together with one or more inserted atoms, they can optionally be linked to form a fused ring structure. In some embodiments, m can be 0, 1, 2, or 3. For example, in some embodiments, m is 0, i.e., the phenyl group is unsubstituted. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, R 101 Each time it appears, it is independently F, OH, CN, C.1-4 Alkyl (e.g., methyl, ethyl, propyl, etc.), cyclopropyl, cyclobutyl, oxetane, C 1-4 Alkyl groups (e.g., methoxy groups), fluorine-substituted C groups 1-4 Alkoxy groups (e.g., fluorinated methoxy groups), fluorinated C 1-4 Alkyl groups (e.g., fluorinated methyl groups, such as CF2H, or fluorinated ethyl groups, such as CH2CF2H). In some embodiments, R 101 Each time it appears, it is independently F or C. 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, etc.), OH, cyclopropyl, cyclobutyl, oxetyl, or CN.

[0207] In any implementation thereof, unless otherwise stated or contrary to the context, in Equation I-5, R 2 You can choose from:

[0208]

[0209] In some preferred embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-5, wherein R 2 It can also be a 5-10 membered heteroaryl group having 1-4 independently selected cyclic heteroatoms chosen from N, O, and S, optionally by one or more (e.g., 1, 2, or 3) independently selected from 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 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The heteroaryl group is substituted with a substituent; and the two optional substituents of the heteroaryl group, together with one or more inserted atoms, may optionally be linked to form a fused ring structure.

[0210] In some preferred embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-5, wherein R 2 It can be a 5- or 6-membered heteroaryl group having 1 to 4 cyclic heteroatoms independently selected from N, O, and S, such as pyridinyl (e.g., 2-, 3-, or 4-pyridinyl), pyrazole, etc., which is optionally independently selected by one or more (e.g., 1, 2, or 3) cyclic heteroatoms from 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 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C.1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The substituents of the heteroaryl group are substituted; and the two optional substituents of the heteroaryl group, together with one or more inserted atoms, may optionally be linked to form a fused ring structure. For example, in some embodiments, in formula I-5, R 2 Can be selected

[0211] In some preferred embodiments, compounds having formula I (e.g., formula IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10) can be characterized as having formula I-5, wherein R 2 It can be an 8-10 membered bicyclic heteroaryl group having 1-4 cyclic heteroatoms independently selected from N, O, and S, such as indole, indazole, etc., which is optionally composed of one or more (e.g., 1, 2, or 3) independently selected from 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 Substituents of ) where G1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl; wherein G 2 Each time it appears independently, it is a 4-6 membered heterocyclic group, phenyl, or 5- or 6-membered heteroaryl group having 1-2 cyclic heteroatoms independently selected from N, O, and S, wherein each is optionally composed of 1-3 cyclic heteroatoms independently selected from oxo (if applicable), F, CN, G. 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 The heteroaryl group is substituted with a substituent; and the two optional substituents of the heteroaryl group, together with one or more inserted atoms, may optionally be linked to form a fused ring structure.

[0212] In some preferred embodiments, compounds having formula I-5 can be characterized as having formula I-5-1 or I-5-2:

[0213]

[0214] Where L 1 R 1 R 3 R 4 m and R 101 This includes any of those described herein in any combination.

[0215] Multiple groups are applicable to R in Formula I 3 For example, in some implementations, R 3 It is hydrogen. In some implementations, R 3 It is a halogen (e.g., F). In some embodiments, R 3 It is CN. In some implementations, R 3 It is C(O)NR 11 R 12 , where R 11 and R 12 Defined in this document, for example, R 11 and R 12 It can be hydrogen at the same time. In some embodiments, R 3 C is arbitrarily replaced 3-8 Carbocyclic group. In some embodiments, R 3It is a 4-10 membered heterocyclic group having one or two independently substituted cyclic heteroatoms selected from N, O, and S. In some embodiments, R 3 It is a 5-10 membered heteroaryl group having 1-4 independently selected cyclic heteroatoms chosen from N, O and S, which are optionally substituted.

[0216] In any implementation herein, unless otherwise stated or contrary to the context, R in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, or IB) 3 It can be hydrogen, F, Cl, Br, or C optionally substituted with F. 1-4 Alkyl, or CN. For example, in some embodiments, compounds having formula I can be characterized as having a formula according to: IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, or IA-10B.

[0217]

[0218]

[0219] Where L 2 L 3 R 2 R 10 R 11 and R 12 Includes any of those described herein in any combination. In some embodiments according to formulas IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, or IA-10A, R 11 and R 12 C is independently hydrogen, optionally substituted with F and / or deuterium. 1-4 Alkyl groups, or C groups optionally substituted with F and / or deuterium. 3-6 Cycloalkyl. In some embodiments according to formula IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, or IA-10A, R 11 and R 12 One of them is hydrogen, and R 11 and R 12 The other is hydrogen, C optionally replaced by F and / or deuterium. 1-4 Alkyl groups, or C groups optionally substituted with F and / or deuterium.3-6 Cycloalkyl. In some preferred embodiments according to formula IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, or IA-10A, R 11 and R 12 One of them is hydrogen, and R 11 and R 12 The other one is hydrogen, methyl, CD3, ethyl, isopropyl, cyclopropyl, cyclobutyl, In some preferred embodiments according to formulas IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, or IA-10B, R 10 C is a C that can be arbitrarily replaced by 1-3 Fs. 1-4 Alkyl groups, such as CH3, CH2F, CF3, etc. In some preferred embodiments according to formulas IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, or IA-10B, R 10 It is a 5- or 6-membered heteroaryl group having 1-3 independently selected cyclic heteroatoms from N, O, and S, such as pyrazole, imidazole, triazole, etc., which can be optionally substituted, for example by C. 1-4 Alkyl (e.g., methyl) substitution, for example

[0220]

[0221] In some embodiments, R in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, or IB) 3 C can be arbitrarily replaced 1-4 Alkyl group. In some embodiments, R 3 It can be optionally selected by one or more, for example, 1-3 independently selected from deuterium, F, CN, or OR. C The substituents of C 1-4 Alkyl, wherein R C Each time it appears, it is independently and optionally selected from 1-3 independent elements: deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. For example, in some embodiments, R 3It can be methyl, CD3, CH2-OMe, CH2-OCD3, ethyl, CHF2, CF2CH3, CH2CH2F, CH2CF2H, or CF3.

[0222] In some embodiments, R in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, or IB) 3 C can be arbitrarily replaced 2-4 alkenyl, for example

[0223] In some embodiments, R in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, or IB) 3 C can be arbitrarily replaced 2-4 alkynyl groups, for example

[0224] In some embodiments, R in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, or IB) 3 It can be OR A For example, in some implementations, R 3 OR A And R A It is hydrogen, optionally composed of 1-3 independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

[0225] In some embodiments, R in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, or IB) 3 It can be C(O)R B For example, in some implementations, R 3 It is C(O)R B And R B It is hydrogen, optionally composed of 1-3 independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

[0226] In some embodiments, R in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, or IB) 3 It can also be C 3-6 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), 4-6 membered heterocyclic groups (e.g., oxocyclobutyl, tetrahydrofuranyl) having 1-2 independently selected cyclic heteroatoms chosen from N, O, and S, or 5-6 membered heteroaryl groups (e.g., thiazolyl) having 1-4 independently selected cyclic heteroatoms chosen from N, O, and S, each of which is optionally composed of 1-3 independently selected oxo (if applicable), deuterium, F, CN, G 1 OH, OG 1 NH2, NH(G) 1 ), N(G 1 (G) 1 ), C(O)-NH2, C(O)-NH(G) 1 ), and C(O)-N(G 1 (G) 1 Substituents of ) where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6Cycloalkyl.

[0227] In any implementation herein, unless otherwise stated or contrary to the context, R in Equation I (e.g., Equations I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, or IB) 3 You can choose from:

[0228]

[0229] R in Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, or IB) 4 Typically, it is hydrogen. In some embodiments, R in Formula I... 4 It can also be a halogen (e.g., F), or optionally substituted C. 1-6 Alkyl, or NR 11 R 12 For example, in some implementations, R in Formula I 4 It is NH2.

[0230] In some implementations, in Formula I (e.g., Formula IA, IA-1, IA-2, IA-3, IA-4, or IB), L, when applicable 2 and R 3 Together with the inserted atoms, they can also be linked to form optionally substituted 4-8 membered ring structures, such as 4-8 membered heterocyclic structures or 5- or 6-membered heteroaryl structures.

[0231] In some embodiments, in formula I (e.g., formulas I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, or IB), when applicable, R 3 and R 4Together with the inserted atoms, they can also be linked to form optionally substituted 4-8 membered ring structures, such as 4-8 membered heterocyclic structures or 5- or 6-membered heteroaryl structures. For example, in any embodiment herein, unless otherwise stated or contrary to the context, in formula I (e.g., formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, 1A, 1A-1, 1A-2, 1A-3, 1A-4, or IB), R 3 and R 4 Together with the inserted atoms, they can connect to form one of the following:

[0232]

[0233] In some embodiments, this disclosure provides compounds having Formula II or pharmaceutically acceptable salts thereof:

[0234]

[0235] in:

[0236] L 1 It is an optionally substituted arylene (e.g., phenylene), an optionally substituted heteroarylene (e.g., 5- or 6-membered heteroarylene), an optionally substituted heterocyclic group (e.g., 4-8-membered heterocyclic group), or an optionally substituted carbocyclic group (e.g., C10-C ... 3-8 (subcarbocyclic group);

[0237] R 1 It is SO2R 10 SO2NR 11 R 12 S(O)(NH)R 10 、or C(O)NR 11 R 12 ; or R 1 Is it hydrogen or NR? 11 R 12 ;

[0238] X is N or CR 13 ;

[0239] Ring A is a carbon ring or a heterocycle that has one or more (e.g., 1 or 2) independently selected cyclic heteroatoms chosen from O, N and S, which are optionally substituted.

[0240] Q is hydrogen, OR A C, which is arbitrarily replaced 1-4 Alkyl, halogen, CN, or COR B ;

[0241] R 3 It is hydrogen, halogens (e.g., F), CN, C(O)NR 11 R 12 C, which is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 alkynyl group, optionally substituted C 1-4 Heteroalkyl, OR A COR B COOR A NR 11 R 12 C, which is arbitrarily replaced 3-8 Carbocyclic group, optionally substituted 4-10-membered heterocyclic group, or optionally substituted 5-10-membered heteroaryl group;

[0242] R 4 It is hydrogen, halogen (e.g., F), or optionally substituted C. 1-6 Alkyl, or NR 11 R 12 ;

[0243] Or R 3 and R 4 Together with the inserted atoms, they form optional 4-8 membered ring structures;

[0244] in:

[0245] R 10 C is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5-membered or 6-membered heteroaryl group), or optionally substituted 4-10-membered heterocyclic group;

[0246] R 11 and R 12 Each of them, each time it appears, is independently hydrogen, optionally substituted C. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl group), optionally substituted 4- to 10-membered heterocyclic group; or nitrogen protecting group; or R 11 and R 12 They can be linked to form optionally substituted 4-10 member heterocyclic groups or 5- or 6-membered heteroaryl groups;

[0247] R A Each time it appears, it is independently hydrogen, optionally substituted C. 1-6 Alkyl groups, optionally substituted C3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl group), optionally substituted 4- to 10-membered heterocyclic group; or oxygen protecting group;

[0248] R B Each time it appears, it is independently hydrogen, optionally substituted C. 1-6 Alkyl groups, optionally substituted C 3-8 Carbocyclic group, optionally substituted phenyl group, optionally substituted 4-10 membered heterocyclic group, or optionally substituted heteroaryl group (e.g., 5- or 6-membered heteroaryl group); and

[0249] R 13 It is hydrogen, F, CN, -OH, or optionally substituted C. 1-4 Alkyl groups, optionally substituted C 1-4 Heteroalkyl groups, optionally substituted C 3-8 Carbocyclic group, or optionally substituted 4-10 membered heterocyclic group.

[0250] For clarity, ring A as drawn in Formula II (including any applicable sub-formulas) should be understood as comprising at least two cyclic carbon atoms respectively attached to the O atom and Q group as drawn in Formula II.

[0251] In some embodiments, compounds having Formula II (including any applicable sub-formulas described herein) can exist in a variety of stereoisomeric forms (e.g., enantiomers and / or diastereomers). In some embodiments, compounds having Formula II can exist as individual enantiomers and / or diastereomers (if applicable), or mixtures of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). In some embodiments, when applicable, compounds having Formula II (including any applicable sub-formulas described herein) can exist as individual enantiomers that are substantially free of (e.g., less than 20%, less than 10%, less than 5%, less than 1% by weight, or have undetectable amounts, by HPLC or SFC area or both). In some embodiments, when applicable, compounds having Formula II (including any applicable sub-formulas described herein) can also exist as mixtures of stereoisomers (in any ratio), such as racemic mixtures.

[0252] It will be apparent to those skilled in the art that, in certain circumstances, compounds having Formula II can exist as mixtures of tautomers. This disclosure is not limited to any particular tautomer. Rather, this disclosure covers any and all such tautomers, whether or not explicitly drawn or mentioned.

[0253] In some embodiments, compounds having Formula II (including any applicable sub-formulas as described herein) may exist as isotopically labeled compounds, particularly deuterated analogs, wherein one or more hydrogen atoms of the compound having Formula II are replaced by deuterium atoms with an abundance higher than their native abundance, for example, CD3 analogs when the compound has a CH3 group.

[0254] Typically, X in Formula II is N, and compounds having Formula II can be characterized as having Formula II-A:

[0255]

[0256] Where L 1 R 1 Ring A, Q, R 3 and R 4 This includes any of those described herein in any combination. For example, variable L 1 R 1 R 3 and R 4 It can include any of those defined herein that are associated with Equation I in any combination form.

[0257] Various ring structures are suitable as ring A in Formula II. For example, in some embodiments, ring A is an optionally substituted C having 1-4 independently selected cyclic heteroatoms chosen from O, S, and N. 4-10 Cycloalkyl or optionally substituted 4-10 membered heterocycles. Ring A can be monocyclic or polycyclic, and can include fused, bridged, or spirocyclic structures. For example, in some embodiments, ring A can be an optionally substituted monocyclic C 4-8 Cycloalkyl, such as C4, C5, C6, or C7 cycloalkyl. In some embodiments, ring A is optionally substituted fused, bridged, or spirobicyclic C. 6-10 Cycloalkyl groups, such as those described herein. In some embodiments, ring A may be a substituted monocyclic 4-8-membered heterocycle, such as those having one cyclic heteroatom selected from O and N. In some embodiments, ring A is a substituted fused, bridged, or spirobicyclic 6-10-membered heterocycle, such as those having one or two cyclic heteroatoms independently selected from O, S, and N. When further substituted, ring A can typically be 1-3 independently selected from oxo, halogen (e.g., F), CN, G 1 C(O)H, C(O)G 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 Substituents of ) where G 1Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some embodiments, ring A may also be deuterated, for example, one or more of the cyclic CH2 groups are replaced by CD2 groups.

[0258] Various groups are suitable as Q in Formula II. In some embodiments, Q is OR A For example, in some implementations, Q is OR A , where R A It is hydrogen, optionally composed of 1-3 independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some preferred embodiments, Q in formula II (e.g., any applicable sub-formula) is OH.

[0259] In some implementations, Q can be C, which may be optionally replaced. 1-4 Alkyl groups, such as fluorinated C4 groups 1-4 alkyl or hydroxy substituted C 1-4 Alkyl groups, for example, CH2OH.

[0260] In some embodiments, Q can be a halogen, such as F or CN. In some embodiments, Q can also be COR. B For example, in some implementations, Q is COR. B , where R B It is hydrogen, optionally composed of 1-3 independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

[0261] In some implementations, Q can be F, CN, C(O)H, C(O)- (C optionally replaced by F) 1-4 Alkyl groups), CH2OH, and C groups optionally substituted with F. 1-4 Alkyl groups, or C groups optionally substituted with F. 1-4 Alkyl group.

[0262] In some implementations, formula II (e.g., II-A) You can choose from:

[0263]

[0264] In some implementations, formula II (e.g., II-A) You can choose from:

[0265]

[0266] In some preferred embodiments, formula II (e.g., II-A) You can choose from:

[0267]

[0268] In some preferred embodiments, formula II (e.g., II-A) You can choose from:

[0269]

[0270] In some embodiments, compounds having formula II can be characterized as having a sub-formula, formula II-1 or II-2, or a deuterated analogue thereof:

[0271]

[0272] in:

[0273] n1 and n2 are independently 0, 1, 2 or 3.

[0274] Z is CR 21 R 22 , O or NR 23 ,

[0275] When the valence is allowed, p can be 0, 1, 2, 3, or 4.

[0276] R 20 Each occurrence is independently of oxidative, halogen (e.g., F), CN, G. 1 C(O)H, C(O)G 1 OH, OG 1 NH2, NH(G) 1 ), and N(G 1 (G) 1 ), where G 1 Each time it appears, it is independently and optionally selected from 1-3 independent elements: F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4Alkyl groups, or optionally alkyl groups independently selected from F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 cycloalkyl,

[0277] Or two R 20 Forming an oxo group, or two R groups 20 Together with the inserted atoms, they form optionally substituted ring structures.

[0278] R 21 and R 22 Each is independently hydrogen or R 20 ,

[0279] or R 21 and R 22 Together they form a ring structure in which oxo groups are optionally substituted.

[0280] or R 21 and R 22 One and one R 20 The group, together with the inserted atom, forms an optionally substituted ring structure, R 23 Is it hydrogen or R? 20 ,

[0281] or R 23 And an R 20 The group, together with the inserted atom, forms an optionally substituted ring structure.

[0282] Among them, Q and L 1 R 1 R 3 and R 4 This includes any of those described herein in any combination.

[0283] For clarity, variable R 21 R 22 and R 23 Although it can be used with R 20 It has the same definition, but does not include R plotted in Equation II-1 or II-2. 20 The number of groups. In other words, the integer p refers to the potential substitution of the ring at any available position except for the Z group.

[0284] Typically, n2 in equation II-1 or II-2 is 1.

[0285] Typically, n1 in equation II-1 or II-2 is 0, 1, or 2.

[0286] In some implementations, n1 and n2 make the ring a 4-8 element ring, such as a 4, 5, 6 or 7 element ring.

[0287] In some embodiments, Z in formula II-1 or II-2 is CH2, O, or NR. 23 , where R 23 It is a C that is hydrogen or optionally substituted with 1-3 independent substituents selected from F, CN, and OH. 1-4 alkyl.

[0288] In some preferred embodiments, Z in formula II-1 or II-2 is CH2.

[0289] In some preferred embodiments, Z in formula II-1 or II-2 is CF2.

[0290] Compounds having formula II-1 or II-2 may exist in a deuterated form. For example, in some preferred embodiments, the hydrogen on the Z group may be replaced with deuterium; in other words, the Z group in formula II-1 or II-2 may be CD2.

[0291] In some preferred embodiments, Z in formula II-1 or II-2 is O.

[0292] The integers in formula II-1 or II-2 are typically 0-2. For example, in some embodiments, p in formula II-1 or II-2 is 0. In some embodiments, p in formula II-1 or II-2 is 1 or 2.

[0293] In some implementations, p in formula II-1 or II-2 is 1 or 2, R 20 Each occurrence is independently of a halogen (e.g., F), CN, G. 1 C(O)H, C(O)G 1 OH or OG 1 For example, in some embodiments, p in formula II-1 or II-2 is 1 or 2, and R 20 Each occurrence is independently of a halogen (e.g., F), CN, G. 1 C(O)H, C(O)G 1 OH or OG 1 G 1 C is a C that can be arbitrarily replaced by 1-3 Fs. 1-4 alkyl.

[0294] Various groups are suitable for use as Q in Formula II-2, including any definition of Q as described herein. In some embodiments, Q in Formula II-2 may be F, CN, C(O)H, C(O)- (C optionally substituted with F) 1-4 Alkyl groups), CH2OH, and C groups optionally substituted with F. 1-4 Alkyl groups, or C groups optionally substituted with F. 1-4 Alkyl group.

[0295] In some preferred embodiments, in formula II-1 The excerpt can be selected from:

[0296]

[0297] In some preferred embodiments, in formula II-1 The excerpt can be selected from:

[0298]

[0299] In some preferred embodiments, in formula II-1 The fragment is In some preferred embodiments, in formula II-1 The fragment is In some preferred embodiments, in formula II-1 The fragment is In some preferred embodiments, in formula II-1 The fragment is In some preferred embodiments, in formula II-1 The fragment is In some preferred embodiments, in formula II-1 The fragment is In some preferred embodiments, in formula II-1 The fragment is In some preferred embodiments, in formula II-1 The fragment is In some preferred embodiments, in formula II-1 The fragment is In some implementations, in formula II-1 The fragment is In some preferred embodiments, in formula II-1 The fragment is In some implementations, in formula II-1 The fragment is In some implementations, in formula II-1 The fragment is

[0300] Compounds having formula II-1 or II-2 can exist in a variety of stereoisomeric forms, such as racemic forms, substantially pure single stereoisomers, mixtures rich in one or more stereoisomers, or mixtures of stereoisomers (in any ratio). For example, in some embodiments, compounds having formula II-1 can be characterized as having formula II-1-S1, II-1-S2, II-1-S3, or II-1-S4:

[0301]

[0302] Among them, the variables are n1, n2, Z, and R. 20 p, L 1 R 1 R 3 and R 4 This includes any of those described herein in any combination. In some embodiments, a compound having any one of formula II-1-S1, II-1-S2, II-1-S3, or II-1-S4 may exist as substantially pure stereoisomers (each plotted stereoisomer), for example, substantially free of (e.g., less than 10%, less than 5%, less than 1%, or undetectable amounts by weight and / or by HPLC or SFC area) other potential stereoisomers. For example, in some embodiments, a compound having formula II-1-S1 may be substantially pure stereoisomers, wherein, among the four potential stereoisomers, the combined amounts of the corresponding stereoisomers having formulas II-1-S2, II-1-S3, and II-1-S4 that may be present, by weight and / or by HPLC or SFC area, are less than 10%, less than 5%, less than 1%, or undetectable amounts. In some embodiments, compounds having formula II-1 may also be present as mixtures of any two or more of the corresponding formulas II-1-S1, II-1-S2, II-1-S3, or II-1-S4 (in any ratio), such as racemic mixtures of II-1-S1 and II-1-S2 or racemic mixtures of II-1-S3 and II-1-S4. Exemplary methods for separating stereoisomers are shown in the Examples section of this document. In some preferred embodiments, compounds having formula II-1 may be characterized as cis isomers, which may be present as stereoisomers of the corresponding formulas II-1-S1 or II-1-S2 or mixtures thereof (in any ratio), such as racemic mixtures or mixtures rich in stereoisomers of formula II-1-S1 or II-1-S2, for example having an enantiomer excess of about 50% or higher, such as about 80% or higher, about 90% or higher, or about 95% or higher.

[0303] In some embodiments, compounds having formula II-2 can be characterized as having formula II-2-S1, II-2-S2, II-2-S3, or II-2-S4:

[0304]

[0305] Among them, the variables are n1, n2, Z, and R. 20 p, Q, L 1 R 1 R 3 and R 4 This includes any of those described herein in any combination. In some embodiments, a compound having any one of formula II-2-S1, II-2-S2, II-2-S3, or II-2-S4 may exist as substantially pure stereoisomers (each plotted stereoisomer), for example, substantially free of (e.g., less than 10%, less than 5%, less than 1%, or undetectable amounts by weight and / or by HPLC or SFC area) other potential stereoisomers. For example, in some embodiments, a compound having formula II-2-S1 may be substantially pure stereoisomers, wherein, among the four potential stereoisomers, the combined amounts of the corresponding stereoisomers having formulas II-2-S2, II-2-S3, and II-2-S4 that may be present, by weight and / or by HPLC or SFC area, are less than 10%, less than 5%, less than 1%, or undetectable amounts. In some embodiments, compounds having formula II-2 may also be present as mixtures of any two or more of the corresponding formulas II-2-S1, II-2-S2, II-2-S3, or II-2-S4 (in any ratio), such as racemic mixtures of II-2-S1 and II-2-S2 or racemic mixtures of II-2-S3 and II-2-S4. Exemplary methods for separating stereoisomers are shown in the Examples section of this document. In some preferred embodiments, compounds having formula II-2 may be characterized as cis isomers, which may be present as stereoisomers of the corresponding formula II-2-S1 or II-2-S2 or mixtures thereof (in any ratio), such as racemic mixtures or mixtures rich in stereoisomers of formula II-2-S1 or II-2-S2, for example having an enantiomer excess of about 50% or higher, such as about 80% or higher, about 90% or higher, or about 95% or higher.

[0306] For equation II and any applicable sub-equations, variable L 1 R 1 R 3 and R 4This includes any of those described herein in any combination, and also includes any of those described herein with respect to Formula I and its sub-formulas. For example, in some embodiments, L in Formula II (e.g., II-A, II-1, or II-2) 1 -R 1 You can choose from: Or L 1 -R 1 yes In some implementations, L in formula II (e.g., II-A, II-1, or II-2) 1 -R 1 Selected from:

[0307]

[0308] In some implementations, L in formula II (e.g., II-A, II-1, or II-2) 1 -R 1 Selected from:

[0309]

[0310] In some implementations, L in formula II (e.g., II-A, II-1, or II-2) 1 -R 1 Selected from:

[0311]

[0312] In some implementations, R in formula II (e.g., II-A, II-1, or II-2) 3 It is a carbon that is hydrogen, F, Cl, Br, or optionally substituted with deuterium and / or F. 1-4 Alkyl, or CN. For example, in some embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 C can be optionally replaced by 1-3 Fs. 1-4 Alkyl groups, such as methyl, CD3, ethyl, CHF2, CF2CH3, CH2CH2F, CH2CF2H, or CF3. In some embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 It can be methyl, CD3, CH2-OMe, CH2-OCD3, ethyl, CHF2, CF2CH3, CH2CH2F, CH2CF2H, or CF3. In some embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 OR A , where R ADefined in this document, for example, R A It is hydrogen, optionally composed of 1-3 independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 It is C(O)R B , where R B Defined in this document, for example, R B It is hydrogen, optionally composed of 1-3 independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl. In some embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 Selected from In some preferred embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 It is CN. In some preferred embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 It is F, Cl, or Br. In some preferred embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 It is CF3. In some preferred embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 It is methyl or ethyl. In some preferred embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 It is CHF2, CF2CH3, CH2CH2F, or CH2CF2H. In some preferred embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 It is cyclopropyl. In some preferred embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 yes In some preferred embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 yes Typically, R in formula II (e.g., II-A, II-1, or II-2) 4 It is hydrogen. In some implementations, R 4 It can be NH2. In some embodiments, R in formula II (e.g., II-A, II-1, or II-2) 3 and R 4 It can be linked to form a 5- or 6-membered heteroaryl structure (the 5- or 6-membered heteroaryl structure having 1-3 cyclic heteroatoms independently selected from N, O, and S), optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from F, CN, and OH, and a 4- or 6-membered heterocyclic group (the 4- or 6-membered heterocyclic group having 1-2 cyclic heteroatoms independently selected from N, O, and S), optionally substituted by 1-3 substituents independently selected from oxo, F, CN, and OH. For example, in some embodiments, R 3 and R 4 Connect to form

[0313]

[0314] In some embodiments, this disclosure also provides compounds selected from Table 1A or Table 1B below, their deuterated analogs, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0315] Table 1A. List of Compounds

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323] Table 1B. List of Compounds

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335] The compounds in Tables 1A and 1B can exist in a variety of stereoisomeric forms, such as individual isomers, individual enantiomers and / or diastereomers (if applicable), or mixtures of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). In some embodiments, when applicable, the compounds shown in Tables 1A or 1B can exist as individual enantiomers that are substantially free of (e.g., less than 20%, less than 10%, less than 5%, less than 1% by weight, or have undetectable amounts, by HPLC or SFC area or both) other enantiomers. In some embodiments, when applicable, the compounds shown in Tables 1A or 1B can also exist as mixtures of stereoisomers (in any ratio), such as racemic mixtures.

[0336] In some embodiments, to the extent applicable, the compound categories described herein also exclude any single compound specifically known prior to this disclosure. In some embodiments, to the extent applicable, any subclass or species of compound that previously belonged entirely to the compound categories described herein may also be excluded from this category of compounds.

[0337] Synthesis method

[0338] In view of this disclosure, those skilled in the art can readily synthesize the compounds disclosed herein. Exemplary synthesis is also shown in the Examples section.

[0339] The synthesis of compounds having Formula I shown in Scheme 1 is illustrative. As shown in Scheme 1, compounds having Formula I can typically be prepared from compound S-2 via a series of coupling reactions. For example, in some embodiments, compound S-2 may first react with amine S-1 to form compound S-3. Typically, G in S-2... 1A It is a leaving group as described herein, such as a halogen, like Cl, and G in S-1 1BTypically, it is hydrogen. The conditions for coupling compounds S-1 and S-2 include any conditions known for similar conversions. Exemplary conditions are shown in the Examples section of this document. Compound S-3 can then react with S-4 to form a compound having formula I. Typically, G in S-3 2A It is a leaving group as described herein, such as a halogen, such as F, Cl, and when L 2 Is it O or NR? 14 , or when R 2 -L 3 -L 2 When representing a heterocycle connected to a pyridine or pyrimidine ring in Formula I via a cyclic nitrogen ring, G in S-4 2B Typically, it is hydrogen. The conditions for coupling compounds S-3 and S-4 include any conditions known for similar conversions. Exemplary conditions are shown in the Examples section of this document. In some embodiments, G in S-3... 2A It can be a leaving group as described herein, such as a halogen, and G in S-4 2B Coupling partners such as borate / ester, tin, and zinc can be used, allowing S-4 to react with S-3 under appropriate conditions (e.g., palladium-catalyzed cross-coupling) to introduce R. 2 -L 3 -L 2 Group. The variable L in Scheme 1. 1 L 2 L 3 R 1 R 2 R 3 R 4 X includes any of those described herein in any combination. Although Scheme 1 describes a specific sequence of coupling various compounds with S-2 to provide a compound having Formula I, this disclosure is not limited to such a coupling sequence. For example, in some embodiments, the synthetic method may couple S-2 with S-4 to form R. 2 -L 3 -L 2 A group is introduced, and the resulting compound is then sequentially coupled with S-1 and S-4 to provide a compound having formula I. Compound S-2 may be commercially available and can typically be prepared according to various heteroaryl formation methods and / or subsequent transformations known in the art. Coupling partners S-1 and S-4 are typically commercially available or, in view of this disclosure, readily prepared by those skilled in the art.

[0340] Option 1

[0341]

[0342] As will be apparent to those skilled in the art, conventional protecting groups are necessary to protect certain functional groups from undesirable reactions. Suitable protecting groups for various functional groups, and suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in "Protective Groups in Organic Synthesis," 4th edition, PGMWuts; TW Greene, John Wiley, 2007, and the references cited therein. The reagents used in the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Other reagents can be prepared by procedures described in the following standard reference texts or by obvious modifications thereof: for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry (Wiley, 7th edition); and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), and any available updated versions up to this application.

[0343] Pharmaceutical Composition

[0344] Some embodiments involve pharmaceutical compositions comprising one or more compounds disclosed herein.

[0345] The pharmaceutical composition may optionally comprise a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises compounds disclosed herein (e.g., compounds having Formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, I...). A-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), and pharmaceutically acceptable excipients. 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, coating agents, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's *The Science and Practice of Pharmacy*, 21st edition, ARGennaro (Lipincott, Baltimore, MD: Williams & Wilkins, 2005; incorporated herein by reference), which discloses a variety of excipients for formulating pharmaceutical compositions and known techniques for preparing pharmaceutical compositions.

[0346] The pharmaceutical composition may comprise any one or more compounds disclosed herein. For example, in some embodiments, the pharmaceutical composition comprises, for example, a therapeutically effective amount of a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, ... The pharmaceutical composition may comprise a compound having Formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof. In any embodiment described herein, the pharmaceutical composition may comprise a therapeutically effective amount (e.g., for the treatment of breast or ovarian cancer) of a compound selected from any of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the pharmaceutical composition may comprise compounds selected from those according to Examples 1-155, having a CDK2 / cyclin E1 IC50 level designated as “A” or “B”, preferably “A”, in Table 2 herein.

[0347] The pharmaceutical compositions described herein can be formulated for delivery via any known route of delivery, including but not limited to oral, nasal, percutaneous, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral administration.

[0348] In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulation can exist in discrete units, such as capsules, pills, tablets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients used to prepare the oral administration composition are known in the art. Suitable, non-limiting excipients include, for example, agar, alginate, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butanediol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, and peanut oil. Oil), potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearic fumarate, sucrose, surfactant, talc, astragalus gum, tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof.

[0349] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). Parenteral formulations may be, for example, aqueous solutions, suspensions, or emulsions. Excipients used to prepare parenteral formulations are known in the art. Suitable, non-limiting excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, wheat germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0350] The compounds disclosed herein can be used alone, in combination with each other, or in combination with one or more other therapeutic agents, such as other anticancer therapeutic agents, such as mitosis inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormones and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors (e.g., protein tyrosine kinase and / or serine / threonine kinase inhibitors), cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immunotumor agents, etc. In some embodiments, one or more of the compounds disclosed herein may be used in combination with one or more targeting agents, such as inhibitors of PI3 kinase, mTOR, PARP, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, Src / Abl, RTK / Ras, Myc, Raf, PDGF, AKT, c-Kit, erbB, CDK4 / CDK6, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1, EZH2, or Hsp90, or immunomodulators, such as PD-1 or PD-L1 antagonists, OX40 agonists, or 4-1BB agonists. In some embodiments, one or more of the compounds disclosed herein may be used in combination with standard therapeutic agents, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole, or trastuzumab. Suitable additional anticancer therapeutic agents include any of those known in the art, such as those approved by a regulatory agency such as the U.S. Food and Drug Administration for the treatment of suitable cancers. Some examples of suitable additional anticancer therapeutic agents also include those described in WO 2020 / 157652, US 2018 / 0044344, WO 2008 / 122767, etc., the contents of which are incorporated herein by reference in their entirety.

[0351] When used in combination with one or more other therapeutic agents, the compounds disclosed herein or the pharmaceutical compositions herein may be administered to a subject simultaneously or sequentially with such other therapeutic agents in any order. In some embodiments, the pharmaceutical composition may comprise one or more of the compounds disclosed herein and one or more other therapeutic agents in a single composition. In some embodiments, a pharmaceutical composition comprising one or more of the compounds disclosed herein may be included in a kit that also comprises a separate pharmaceutical composition comprising one or more other therapeutic agents.

[0352] Pharmaceutical compositions may comprise various amounts of the compounds disclosed herein, depending on various factors such as the intended use of the compounds and their potency and selectivity. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compounds disclosed herein. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compounds disclosed herein and pharmaceutically acceptable excipients. As used herein, a therapeutically effective amount of a compound disclosed herein is an amount that is effective in treating the disease or disorder described herein, such as breast cancer or ovarian cancer, and may depend on the recipient of treatment, the disorder, condition, or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is administered concurrently.

[0353] Treatment / Usage

[0354] The compounds disclosed herein have a variety of uses. For example, the compounds disclosed herein can be used as therapeutically active substances for the treatment and / or prevention of CDK2-mediated diseases or disorders. Accordingly, some embodiments of this disclosure also relate to methods of treating or preventing CDK2-mediated diseases or disorders in subjects in need, such as treating cancer in subjects in need, using one or more of the compounds disclosed herein or the pharmaceutical compositions herein.

[0355] In some embodiments, this disclosure provides a method for inhibiting abnormal cell growth in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the disclosed compound or the pharmaceutical composition described herein. In some embodiments, the abnormal cell growth is cancer characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some embodiments, the subject is identified as having cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0356] In some embodiments, this disclosure also provides a method for inhibiting CDK activity in a subject or biological sample. In some embodiments, this disclosure provides a method for inhibiting CDK2 activity in a subject or biological sample, the method comprising reacting the subject or biological sample with an effective amount of a compound of the disclosure (e.g., a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9)). A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or contact with the pharmaceutical compositions described herein.

[0357] In some embodiments, this disclosure provides methods for treating or preventing CDK-mediated, particularly CDK2-mediated, diseases or disorders in subjects of need. In some embodiments, the method includes administering to the subject an effective amount of a compound of this disclosure (e.g., a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA...). -6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or an effective amount of the pharmaceutical composition described herein. In some embodiments, the CDK2-mediated disease or disorder is cancer. In some embodiments, the cancer is characterized by the amplification or overexpression of CCNE1 and / or CCNE2.

[0358] In some embodiments, this disclosure also provides a method for treating or preventing cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound of this disclosure (e.g., a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A)). The drug may contain, for example, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or an effective amount of the pharmaceutical composition described herein. In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments, the subject is identified as having cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma, or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric cancer, thyroid cancer, and combinations thereof. In some embodiments of the methods 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.

[0359] In some embodiments of the methods described 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 may be endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer may be advanced or metastatic breast cancer. In some embodiments, the breast cancer described herein is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0360] In some embodiments of the method described herein, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0361] In some embodiments of the methods described herein, the cancer is a blood cancer such as leukemia. In some embodiments of the methods described herein, the cancer is chronic lymphocytic leukemia, such as relapsed or refractory chronic lymphocytic leukemia (CLL).

[0362] In some embodiments of the method described herein, the cancer is acute myeloid leukemia. In some embodiments of the method described herein, the cancer is relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome.

[0363] In any of the embodiments described herein, unless otherwise stated or contradicted, the cancer described herein may be characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0364] In some embodiments, this disclosure also provides a method of treating breast cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, I...). A-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or an effective amount of the 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 exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0365] In some embodiments, this disclosure also provides a method of treating ovarian cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, I...). A-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or an effective amount of the pharmaceutical composition described herein. In some embodiments, the ovarian cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0366] In some embodiments, this disclosure also provides a method of treating leukemia in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, I...). A-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or an effective amount of the pharmaceutical composition described herein. In some embodiments, the leukemia is characterized by the amplification or overexpression of CCNE1 and / or CCNE2.

[0367] In some embodiments, this disclosure also provides a method for treating chronic lymphocytic leukemia, such as relapsed or refractory chronic lymphocytic leukemia (CLL), in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7)). A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or an effective amount of the pharmaceutical composition described herein.

[0368] In some embodiments, this disclosure also provides a method for treating acute myeloid leukemia, such as relapsed or refractory acute myeloid leukemia, in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA- 8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or an effective amount of the pharmaceutical composition described herein.

[0369] In some embodiments, this disclosure also provides a method for treating myelodysplastic syndrome in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound having formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9)). A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), compounds having formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S3, II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any specific compound disclosed in Tables 1A or 1B herein, or a pharmaceutically acceptable salt thereof), or an effective amount of the pharmaceutical composition described herein.

[0370] In some preferred embodiments, the compounds of this disclosure used in the methods herein, as measured / calculated according to Biological Example 1 herein, have a CDK2 / cyclin E1 IC50 of less than 100 nM, more preferably less than 10 nM. In some preferred embodiments, the compounds of this disclosure used in the methods herein are selected from the compounds of Examples 1-155, which have a CDK2 / cyclin E1 IC50 level designated as “A” or “B”, preferably “A”, in Table 2 herein.

[0371] The administration described herein is not limited to any particular route of administration. For example, in some embodiments, the administration may be oral, nasal, percutaneous, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, the administration is oral. In some embodiments, the administration is parenteral injection, such as intravenous injection.

[0372] The compounds disclosed herein can be used as a monotherapy or in combination therapy. In some embodiments of the methods described herein, one or more of the compounds disclosed herein may be administered as the sole or only active ingredient. In some embodiments of the methods described herein, one or more of the compounds disclosed herein may also be administered co-administered with additional therapeutic agents, simultaneously or sequentially to subjects in need. Additional therapeutic agents can typically be other anticancer agents, such as mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormones and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors (e.g., protein tyrosine kinase and / or serine / threonine kinase inhibitors), cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immunotumor agents, etc. In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor, SERD, or SERM. In some embodiments, one or more of the compounds disclosed herein may be administered in combination with one or more targeted agents, such as inhibitors of PI3 kinase, mTOR, PARP, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, Src / Abl, RTK / Ras, Myc, Raf, PDGF, AKT, c-Kit, erbB, CDK4 / CDK6, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1, EZH2, or Hsp90, or immunomodulators, such as PD-1 or PD-L1 antagonists, OX40 agonists, or 4-1BB agonists. In some embodiments, one or more of the compounds disclosed herein may be administered in combination with standard therapeutic agents, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole, or trastuzumab. Suitable additional anticancer therapeutic agents include any of those known in the art, such as those approved by a regulatory agency such as the U.S. Food and Drug Administration for the treatment of suitable cancers. Some examples of suitable additional anticancer therapeutic agents also include those described in WO 2020 / 157652, US 2018 / 0044344, WO 2008 / 122767, etc., the contents of which are incorporated herein by reference in their entirety.

[0373] The dosage regimen, including the methods described herein, can be varied and adjusted depending on the recipient of treatment, the disorder, condition or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is administered concurrently.

[0374] definition

[0375] It should be understood that all fragments and their combinations maintain the appropriate valence.

[0376] It should also be understood that the specific implementation of the variable fragment in this article may be the same as or different from another specific implementation having the same identifier.

[0377] Choose independently the appropriate group for the variable in a compound having Formula I or II or its derivatives. Non-limiting useful groups for the variable in a compound having Formula I or II or its derivatives (if applicable) include any corresponding group, alone or in any combination, as shown in the examples or specific compounds described in Tables 1A or 1B herein. Using the variable R 1 For example, in some embodiments, compounds having formula I or II may include any R shown in the examples or specific compounds described in Tables 1A or 1B herein. 1 R of the group 1 The group, without regard to other variables shown in a particular compound. In some embodiments, compounds having formula I or II may include any R shown in the examples or in the specific compounds described in Tables 1A or 1B herein. 1 R of the group 1 Groups and at least one other variable (e.g., L) of the specific compounds described in examples or in Tables 1A or 1B herein. 1 A combination of ) where R 1 And at least one other variable may be derived from the same compound or different compounds. Any such combination is considered and such combinations are within the scope of this disclosure.

[0378] Implementations of this disclosure described herein may be combined. Such combinations are contemplated and are within the scope of this disclosure. For example, L of Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB) is considered. 1 L 2 L 3 R 1 R 2 R 3 R 4The definition of any one or more of X can be related to L 1 L 2 L 3 R 1 R 2 R 3 R 4 The other one or more of the definitions of X (if applicable), and the compounds obtained by such combinations, are within the scope of this disclosure.

[0379] symbol Whether used as a bond or shown perpendicular to (or otherwise crossed) a bond, it indicates the point where the shown segment is attached to the rest of the molecule. It should be noted that one or more directly connected groups may be shown in the symbol... In addition, it indicates connectivity, as understood by those skilled in the art.

[0380] The following describes the definitions of specific functional groups and chemical terms in more detail. Chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as descriptions of specific functional parts and reactivity, are found in the following: 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. This disclosure is not intended in any way to be limited to the exemplary list of substituents described herein.

[0381] The compounds described herein may contain one or more asymmetric centers and thus 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, or in the form of mixtures of stereoisomers (including racemic mixtures and mixtures rich in one or more stereoisomers). Isomers can be separated from mixtures 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, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (Ellie Liel, ed., Univ. of Notre Dame Press, University of Notre Dame, Indiana, 1972). This disclosure further covers 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 plotted, it should be understood, unless the context contradicts it, that with respect to that particular chiral center or axial chirality, the compound may exist primarily as the plotted stereoisomer, for example, by HPLC or SFC area or both less than 20%, less than 10%, less than 5%, less than 1% by weight, or together with one or more other stereoisomers in undetectable amounts. The presence and / or amount of stereoisomers can be determined by those skilled in the art in accordance with this disclosure, including by using chiral HPLC or chiral SFC.As will be understood by those skilled in the art, when an asterisk (*) is shown in the chemical structures herein, unless contrary to the context, it indicates that the corresponding chiral center is either pure or enriched in any of the enantiomers, or pure or enriched in the drawn enantiomers, for example, by HPLC or SFC area or both, less than 20%, less than 10%, less than 5%, less than 1% by weight, or has an undetectable amount of one or more other stereoisomers. Furthermore, when no specific stereochemistry is drawn and no asterisk (*) is used in the chemical structures, unless contrary to the context, it should be understood that such structures include the corresponding compounds in any stereoisomeric form, including individual isomers substantially free of other isomers, and mixtures of various isomers, including racemic mixtures.

[0382] When listing a range of values, the aim is to cover every value within that range and its subranges. For example, "C 1–6 "Intended to cover C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 And C 5–6 .

[0383] As used herein, the term “one or more compounds disclosed herein” means any compound according to the following: Formula I (e.g., I-1, I-2, I-3, I-4, I-5, I-2-1, I-2-1-S1, I-2-1-S2, I-2-1-S3, I-2-1-S4, I-5-1, I-5-2, IA, IA-1, IA-2, IA-3, IA-4, IA-5A, IA-6A, IA-7A, IA-8A, IA-9A, IA-10A, IA-5B, IA-6B, IA-7B, IA-8B, IA-9B, IA-10B, or IB), Formula II (e.g., II-A, II-1, II-2, II-1-S1, II-1-S2, II-1-S 3. II-1-S4, II-2-S1, II-2-S2, II-2-S3, or II-2-S4), any one of Examples 1-155, or any particular compound disclosed in Tables 1A or 1B herein, one or more isotopically labeled compounds (e.g., deuterated analogs in which one or more hydrogen atoms are replaced by deuterium atoms in abundance greater than their native abundance, e.g., CD3 analogs when the compound has a CH3 group), their possible regioisomers, possible geometric isomers, possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), their tautomers, their conformational isomers, their pharmaceutically acceptable esters, and / or their possible pharmaceutically acceptable salts (e.g., acid addition salts, such as HCl salts, or base addition salts, such as Na salts). For clarity, the compounds in Examples 1-155 refer to the compounds in the Examples section, designated only by integers, such as 1, 2, etc., up to 155, or, where applicable, may be additionally followed by the designation "a", "b", "c", or "d" to represent the corresponding stereoisomers. See, for example, Figures 1-23 and Table A herein. In general, Examples 1-155 should be understood to include Examples numbered 1-155, as well as those examples designated by the Example number followed by "a", "b", "c", or "d". Exemplary synthesis and characterization of Examples 1-155 are shown in the Examples section. Detailed exemplary procedures are shown in the illustrated examples, such as 1-23. Hydrates and solvates of the compounds disclosed herein are considered compositions of this disclosure, wherein one or more compounds are associated with water or a solvent, respectively.

[0384] The compounds disclosed herein may exist in the form of isotopic labeling or isotopic enrichment, containing one or more atoms whose atomic mass or mass number differs from the most abundant atomic mass or mass number found in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, those of other atoms. 2 H, 3 H, 13C 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 this invention.

[0385] As used in this article, the phrases “administration of”, “administering”, or other variations thereof refer to the provision of a compound or a prodrug of a compound to an individual in need of treatment.

[0386] As used herein, the term "alkyl" alone or as part of another group refers to a straight-chain or branched aliphatic saturated hydrocarbon. In some embodiments, an alkyl group may comprise one to twelve carbon atoms (i.e., C64 ... 1-12 Alkyl group (or a specified number of carbon atoms). In one embodiment, the alkyl group is a straight-chain C18 group. 1-10 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-10 Alkyl group. In another embodiment, the alkyl group is a straight-chain C 1-6 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-6 Alkyl group. In another embodiment, the alkyl group is a straight-chain 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.

[0387] As used herein, the term "alkenyl" alone or as part of another group refers to a straight-chain 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 An alkenyl group. In another embodiment, the alkenyl group is C. 2-4 Alkenyl groups. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0388] As used herein, the term "alkynyl" alone or as part of another group refers to a straight-chain 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 An alkynyl group. In another embodiment, the alkynyl group is C. 2-4 Alkyne group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentylyl, and hexynyl groups.

[0389] As used herein, the term "alkoxy" used alone or as part of another group refers to an alkoxy group having the formula OR a1 The group, wherein R a1 It is an alkyl group.

[0390] As used herein, the term "cycloalkoxy" used alone or as part of another group refers to a group having the formula OR a1 The group, wherein R a1 It is a cycloalkyl group.

[0391] 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, the haloalkyl group is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is C10. 1-10 Halogenated alkyl group. In one embodiment, the halogenated alkyl group is C10. 1-6 Halogenated alkyl group. In one embodiment, the halogenated alkyl group is C10. 1-4 Halogenated alkyl groups.

[0392] As used herein, the term "heteroalkyl," alone or in combination with another term, unless otherwise specified, refers to a stable straight-chain or branched alkyl group, for example, having 2 to 14 carbons in the chain, such as 2 to 10 carbons, one or more of which have been replaced by heteroatoms selected from S, O, P, and N, and wherein nitrogen, phosphine, and sulfur atoms may optionally be oxidized and nitrogen heteroatoms may optionally be quaternized. Heteroatoms S, O, P, and N may be located at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. When a heteroalkyl group is referred to as substituted, one or more substituents may replace one or more carbon atoms and / or one or more hydrogen atoms attached to one or more heteroatoms of the heteroalkyl group. In some embodiments, the heteroalkyl group is C 1-4 Heteroalkyl refers to a heteroalkyl group having 1-4 carbon atoms as defined in this paper. C 1-4Examples of heteroalkyl groups include, but are not limited to, C4 heteroalkyl groups, such as -CH2-CH2-N(CH3)-CH3; C3 heteroalkyl groups, such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -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. Similarly, the term "heteroalkylene" 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 groups, the heteroatom may occupy one or both chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the direction of the linking group. When listing “heteroalkyl” followed by specific heteroalkyl groups, such as “-NR'R”, it should be understood that the terms heteroalkyl and “-NR'R” are not redundant or mutually exclusive. Rather, listing specific heteroalkyl groups increases clarity. Therefore, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as “-NR'R”.

[0393] The term "carbocyclic group" or "carbocyclic" used alone or as part of another group refers to a group having at least 3 carbon atoms, for example, 3 to 10 cyclic carbon atoms ("C"). 3–10 A carbocyclic group is a group that is a non-aromatic cyclic hydrocarbon group having zero heteroatoms in a non-aromatic ring system. The carbocyclic group can be monocyclic (“monocyclic carbocyclic”) or contain a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and can be saturated or partially unsaturated. Non-limiting exemplary carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, naphthane, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term “subcarbocyclic”, used alone or as part of another group, refers to a divalent group derived from a carbocyclic group as defined herein.

[0394] In some embodiments, the "carbocyclic group" is fully saturated, and is also referred to as a cycloalkyl group. In some embodiments, the cycloalkyl group may have 3 to 10 cyclic carbon atoms ("C..."). 3-10 cycloalkyl group (“cycloalkylene”). In a preferred embodiment, the cycloalkyl group is monocyclic. As used herein, the term “cycloalkylene”, used alone or as part of another group, refers to a group derived from a cycloalkyl group, such as… Divalent groups, etc.

[0395] The term "heterocyclic group" or "heterocyclic" as used alone or as part of another group refers to a group having a ternary or larger (e.g., 3- to 14-membered) non-aromatic ring system having a ring carbon atom 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 heterocyclic groups containing one or more nitrogen atoms, the attachment point can be a carbon atom or a nitrogen atom, where the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings, and the attachment point can be on any ring. As used herein, the term "subheterocyclic group" as used alone or as part of another group refers to a divalent group derived from a heterocyclic group as defined herein. Heterocyclic or subheterocyclic groups may optionally be attached to the remainder of the molecule by a carbon or nitrogen atom.

[0396] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirdinyl, ethylene oxide, and thiiranyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridine, oxadiazolinyl, and thiiranyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxapentanyl, oxasulfuranyl, disulfuranyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolidinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiaalkyl, and dioxaneyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxecanyl, and thiocanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0397] The term "aryl" as 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 a cyclic array) that provides 6–14 ring carbon atoms and zero heteroatoms ("C"). 6–14 Aryl group (“C6 aryl”); in some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10"Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms ("C"). 14 "Aryl"; for example, anthracene (as used herein). The term "aryl" as used herein, whether used alone or as part of another group, refers to a divalent group derived from an aryl group as defined herein.

[0398] When used alone or as part of another group, "aralkyl" refers to an alkyl group that is substituted with one or more aryl groups, preferably with one aryl group. Examples of aralkyl groups include benzyl, phenethyl, etc. When aralkyl is referred to as optionally substituted, the alkyl or aryl portion of the aralkyl group may be optionally substituted.

[0399] A “heteroaryl” used alone or as part of another group refers to a group comprising a 5-14 membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., sharing 6 or 10 π electrons in a cyclic array), which provides a cyclic carbon atom and at least one, preferably 1-4, cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups containing one or more nitrogen atoms, the attachment point can be a carbon atom or a nitrogen atom, where the valence allows. A heteroaryl bicyclic system may contain one or more heteroatoms in one or both rings. In a bicyclic heteroaryl group, where one ring does not contain a heteroatom (e.g., indole, quinolinyl, etc.), the attachment point can be on either ring, i.e., the ring carrying the heteroatom (e.g., 2-indole) or the ring without a heteroatom (e.g., 5-indole). As used herein, the term "heteroaryl" used alone or as part of another group refers to a divalent group derived from a heteroaryl group as defined herein.

[0400] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azazolyl. azepinyl, oxo oxepinyl and thiohexyl Thiepinyl groups. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purine. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, 2,3-diazanaphthyl, and quinazolinyl.

[0401] "Heteroarylene" as used alone or as part of another group refers to an alkyl group that is substituted with one or more heteroaryl groups, preferably with one heteroaryl group. When a heteroarylene is referred to as optionally substituted, the alkyl portion or the heteroaryl portion of the heteroarylene may be optionally substituted.

[0402] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the corresponding unsubstituted or substituted group. Generally, the term "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permitted substituent (e.g., a substituent that, upon substitution, produces a stable compound, such as a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reactions)). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents at each position can be the same or different. Typically, when substituted, a group optionally substituted herein can be substituted by 1-5 substituents. Substituents can be carbon, nitrogen, oxygen, or sulfur substituents, and each of them may optionally be isotopically labeled, such as deuterated, if applicable. Two of the optional substituents may link to form a ring structure, such as optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl rings. Substitution can occur on any available carbon, oxygen, or nitrogen atom and can form a spirocyclic ring. Generally, substitutions described herein do not result in OO, ON, SS, SN (except for SO2-N bonds), heteroatom-halogen, or -C(O)-S bonds, or three or more consecutive heteroatoms, except for O-SO2-O, O-SO2-N, and N-SO2-N, unless some such bonds or linkages are permissible in a stable aromatic system.

[0403] In a broad sense, permissible substituents in this document include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms (such as nitrogen) may have hydrogen substituents of the organic compounds described herein and / or any permissible substituents that will satisfy the valence of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, cycloalkoxy groups, phosphoryl groups, phosphate groups, phosphonates, phosphinates, amino groups, amide groups, amidines, imines, cyano groups, nitro groups, azide groups, sulfhydryl groups, alkylthio groups, sulfate groups, sulfonates, sulfamoyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, aryl groups, or heteroaryl groups, each of which may be substituted if applicable.

[0404] Exemplary substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -aryl-alkyl, -alkylene-heteroaryl, -alkenyl-heteroaryl, -alkynyl-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(O)-aryl, halogenated, -NO2, -CN, -SF5, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -S-alkyl -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)2-alkylene-aryl, -S(O)2-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(═N-CN)-NH2, -C(═NH)-NH2, -C(═NH)-NH(alkyl), -N(Y1)(Y2), -alkylene-N(Y1)(Y2), -C(O)N(Y1)(Y2) and -S(O)2N(Y1)(Y2), wherein Y1 and Y2 may be the same or different, and are independently selected from the group consisting of: hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.

[0405] Some examples of suitable substituents include, but are not limited to, (C1-C8) alkyl groups, (C2-C8) alkenyl groups, (C2-C8) alkynyl groups, (C3-C8) alkyl groups, and (C2-C8) alkyne groups. 10Cycloalkyl groups, halogens (F, Cl, Br, or I), halogenated (C1-C8)alkyl groups (e.g., but not limited to -CF3), -O-(C1-C8)alkyl groups, -OH, -S-(C1-C8)alkyl groups, -SH, -NH(C1-C8)alkyl groups, -N((C1-C8)alkyl)2 groups, -NH2, -C(O)NH2, -C(O)NH(C1-C8)alkyl groups, -C(O)N((C1-C8)alkyl)2, -NHC(O)H, -NHC(O)(C1-C8)alkyl groups, -NHC(O)(C3-C8)cycloalkyl groups, -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 (e.g., but not limited to —OCF3), —S(O)2-halogenated (C1-C8)alkyl group Alkyl groups (e.g., but not limited to -S(O)2CF3), -S-halogenated (C1-C8)alkyl groups (e.g., but not limited to -SCF3), -(C1-C6) heterocyclic (e.g., but not limited to pyrrolidine, tetrahydrofuran, pyran, or morpholine), -(C1-C6) heteroaryl (e.g., but not limited to tetrazolium, imidazole, furan, pyrazine, or pyrazole), -phenyl, -NHC(O)O-(C1-C6)alkyl groups, -N((C1-C6)alkyl)C(O)O-(C1-C6)alkyl groups, -C(═NH)-(C1-C6)alkyl groups, -C(═NOH)-(C1-C6)alkyl groups, or -C(═N—O-(C1-C6)alkyl)-(C1-C6)alkyl groups.

[0406] Exemplary carbon substituents include, but are not limited to, deuterium, halogen, –CN, –NO2, –N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3–10 carbonyl group, C 6–10 Aryl, 3–10-membered heterocyclic groups, 5–10-membered heteroaryl groups, etc. For example, exemplary carbon atom substituents may include F, Cl, -CN, –SO2H, –SO3H, –OH, –OC. 1–6 Alkyl, –NH2, –N(C) 1–6 Alkyl)2、–NH(C 1–6 Alkyl), –SH, –SC 1–6 Alkyl, –C(=O)(C 1–6 Alkyl group), –CO2H, –CO2(C 1–6 Alkyl), –OC (=O)(C 1–6 Alkyl), –OCO2(C 1–6 Alkyl groups, –C(=O)NH2, –C(=O)N(C 1–6 Alkyl)2、–OC(=O)NH(C 1–6 Alkyl), –NHC(=O)(C 1–6 Alkyl), –N(C) 1–6 Alkyl)C(=O)(C 1–6 Alkyl), –NHCO2(C 1–6 Alkyl), –NHC(=O)N(C 1–6 Alkyl)2、–NHC(=O)NH(C 1–6 Alkyl groups), –NHC(=O)NH2, –NHSO2(C 1–6 Alkyl), –SO2N(C 1–6 Alkyl)2、–SO2NH(C 1–6 Alkyl groups, –SO2NH2, –SO2C 1–6 Alkyl, –SO2OC 1–6 Alkyl, –OSO2C 1–6 Alkyl, –SOC 1–6 Alkyl, C 1–6 Alkyl, C 1–6 Haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 carbonyl group, C 6–10 Aryl, 3–10 heterocyclic, 5–10 heteroaryl; or two gem substituents can be linked to form =O.

[0407] Nitrogen atoms can be substituted or unsubstituted, provided the valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfones, sulfoxides, and C64. 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 Aryl, and 5–14-membered heteroaryl, or two substituent groups attached to the nitrogen atom to form a 3–14-membered heterocyclic or 5–14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl may be further substituted as defined herein. In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in: Protective Groups in Organic Synthesis, TW Greene and PGM Woods, 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 urethane esters, such as carbobenzyloxy (Cbz) groups, p-methoxybenzyl carbonyl (Moz or MeOZ) groups, tert-butoxycarbonyl (BOC) groups, Troc, 9-fluorenylmethoxycarbonyl (Fmoc) groups, etc.; those that form amides, such as acetyl, benzoyl, etc.; those that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc.; those that form sulfonamides, such as tosyl, Nosyl, etc.; and others such as p-methoxyphenyl.

[0408] Exemplary oxygen substituents include, but are not limited to, acyl groups, esters, sulfonates, and C. 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14Aryl and 5–14-membered heteroaryl groups, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group may be further substituted as defined herein. In some embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also called a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in: Protective Groups in Organic Synthesis, TW Greene and PGM Watts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those that form alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc.; those that form silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), etc.; those that form acetals or ketals, such as tetrahydropyranyl (THP); those that form esters, such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc.; and those that form carbonates or sulfonates, such as methanesulfonate (or mesylate), benzylsulfonate, toluenesulfonate (Ts), etc.

[0409] Unless explicitly stated otherwise, combinations of substituents and / or variables are permitted only if such combinations are chemically permissible and produce stable compounds. A “stable” compound is one whose structure and properties remain or can remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0410] In some embodiments, the "optionally substituted" alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocyclic, carbocyclic, cycloalkylene, cycloalkylene, alkoxy, cycloalkoxy, heterocyclic, or heterocyclic groups may each be independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from the following substituents: deuterium, F, Cl, -OH, protected hydroxyl, oxo (if applicable), NH2, protected amino, NH(C 1-4 Alkyl groups or their protected derivatives, N(C) 1-4 Alkyl ((C) 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, phenyl, 5- or 6-membered heteroaryl groups containing 1, 2, or 3 independently selected cyclic heteroatoms chosen from O, S, and N, or 3- to 7-membered heterocyclic groups containing 1 or 2 independently selected cyclic heteroatoms chosen from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclic groups is optionally substituted by 1, 2, or 3 independently selected substituents chosen from: deuterium, F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl (e.g., CF3), C 1-4 alkoxy and fluorine-substituted C 1-4 Alkoxy. In some embodiments, the “optionally substituted” aryl, arylene, heteroaryl, or heteroarylene groups herein may each be independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected substituents from: deuterium, F, Cl, -OH, -CN, NH2, protected amino, NH(C 1-4 Alkyl groups or their 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 group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, phenyl, 5- or 6-membered heteroaryl groups containing 1, 2, or 3 independently selected cyclic heteroatoms chosen from O, S, and N, or 3- to 7-membered heterocyclic groups containing 1 or 2 independently selected cyclic heteroatoms chosen from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclic groups is optionally substituted by 1, 2, or 3 independently selected substituents chosen from: deuterium, F, -OH, oxo (if applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 alkoxy and fluorine-substituted C 1-4 Alkyl group.

[0411] "Halogen" or "halogen" refers to fluorine (or fluoro, –F), chlorine (or chloro, –Cl), bromine (or bromo, –Br), or iodine (or iodo, –I).

[0412] The term "pharmaceutically acceptable salt" refers to a salt that, to the extent of reasonable medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0413] The term "tautomer" or "tautomerizing" refers to two or more interconvertible compounds resulting from a tautomerization reaction. The exact ratio of tautomers depends on several factors, including, for example, temperature, solvent, and pH. Tautomerization reactions are known to those skilled in the art. Exemplary tautomerization reactions include ketone-to-enol, amide-to-imide, lactam-to-lactam, enamine-to-imide, and enamine-to-(a different)enamine tautomerization reactions.

[0414] As used herein, the term “subject” (which may be referred to as “patient” in this document) refers to an animal, preferably a mammal, and most preferably a human being who has been used as a subject of treatment, observation or experimentation.

[0415] As used herein, the terms "treat," "treating," "treatment," etc., refer to the elimination, reduction, or improvement of a disease or condition and / or its associated symptoms. Although not excluded, treating a disease or condition does not necessarily require the complete elimination of said disease, condition, or its associated symptoms. As used herein, in subjects who do not have but are at risk or prone to developing or relapsing the disease or condition, the terms "treat," "treating," or "treatment," etc., may include "preventive treatment," which refers to reducing the likelihood of disease or condition recurrence or relapse of a previously controlled disease or condition. The term "treatment" and its synonyms are considered to refer to the administration of a therapeutically effective amount of the compound described herein to a subject in need of such treatment.

[0416] The term "effective amount" refers to an amount of a compound or combination of compounds as described herein that is sufficient to achieve the intended application (including, but not limited to, the prevention or treatment of disease). Therapeutic effective amounts can vary depending on: the intended administration (in vitro or in vivo), or the subject and the condition of the disease being treated (e.g., the subject's weight, age, and sex), the severity of the disease, the method of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response in target cells and / or tissues. This specific dose will vary depending on: the specific compound selected, the subsequent dosing regimen (whether or not the compound is combined with other compounds), the time of administration, the tissue to be administered, and the physical delivery system carrying the compound.

[0417] As used in this article, the singular forms “a and an” and “the” include plural references unless explicitly stated or clearly indicated from the context.

[0418] The term "and / or" as used herein, such as in phrases such as "A and / or B," is intended to include A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or" as used herein, such as in phrases such as "A, B, and / or C," is intended to cover each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0419] Titles and subtitles are used for convenience and / or formal compliance only, do not limit the subject matter, and are not associated with the interpretation of the subject matter description. In various embodiments, features described under one title or subtitle disclosed in this subject matter may be combined with features described under other titles or subtitles. Furthermore, all features under a single title or subtitle are not necessarily used together in the embodiments.

[0420] Example

[0421] The various starting materials, intermediates, and compounds described herein can be separated and purified using conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, where appropriate. Characterization of these compounds can be performed using conventional methods, such as melting point analysis, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. The abbreviations used in the Examples section should be understood to have their common meaning in the art, unless otherwise specifically stated or clearly contrary to the context. The examples are illustrative only and do not limit the claimed invention in any way.

[0422] 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 mixtures. As will be understood by those skilled in the art, prior to the chiral separation step, for example by supercritical fluid chromatography (SFC), the compounds described in the Examples section are in the form of racemic and / or stereoisomer mixtures, with relative stereochemistry indicated in the chemical structure diagram using bold instead of wedges. It should be understood that the enantiomer excess (“ee”) reported for these examples represents only the exemplary procedures herein and is not limiting; those skilled in the art will understand that, in light of this disclosure, such enantiomers with different ee, such as higher ee, can be obtained.

[0423] In some illustrative examples, the synthesis of deuterated compounds is shown. It should be understood, within the scope of application, that the corresponding non-deuterated (i.e., naturally abundant) compounds are prepared by the same method, except that they use the corresponding non-deuterated starting materials or intermediates.

[0424] Synthesis of cis-1-methylcyclopentane-1,2-diol (Intermediate I)

[0425]

[0426] Potassium dioxidodioxoosmium dihydrate (2.06 g, 5.60 mmol), 4-methylmorpholine N-oxide (NMO) (18.3 g, 157 mmol), and pyridine (9.0 mL, 112 mmol) were added to a solution of 1-methylcyclopentane-1-ene (IA, 9.20 g, 112 mmol) in t-BuOH (90 mL) and H₂O (30 mL). The reaction mixture was stirred at 85 °C for 5 hours. After completion, the mixture was passed through a small piece of... The solution was filtered through a pad, and the filtrate was quenched with saturated NaHSO3 solution (20 mL). The solution was concentrated under reduced pressure to produce a residue, which was then separated by silica gel column chromatography to provide cis-1-methylcyclopentane-1,2-diol (intermediate I, 11.9 g, 91%) as an oil. 1 H NMR (400MHz, DMSO-d6) δ4.36 (d, J = 5.5Hz, 1H), 3.83 (s, 1H), 3.48-3.34 (m, 1H), 1.81-1.33 (m, 6H), 1.09 (s, 3H).

[0427] Synthesis of cis-4,4-difluoro-1-methylcyclopentane-1,2-diol (intermediate II)

[0428]

[0429] To a mixture of cyclopentan-3-en-1-ol (II-A, 5.00 g, 59.4 mmol) and 1H-imidazole (4.45 g, 65.4 mmol) in DMF (50 mL), trichloroisopropylsilane (11.5 g, 59.4 mmol) was added dropwise. The mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with water (100 mL) and extracted with n-hexane (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give cyclopentan-3-en-1-yloxy)triisopropylsilane (II-B, 14.5 g, crude) as a yellow oil. 1H NMR (500MHz, CDCl3) δ5.68 (s, 2H), 4.67-4.62 (m, 1H), 2.65 (dd, J = 7.0, 1.9Hz, 1H), 2.61 ( dd,J=7.0,1.7Hz,1H),2.37(t,J=2.7Hz,1H),2.33(t,J=2.9Hz,1H),1.13-1.08(m,21H).

[0430] Add potassium osmium tetroxide (0.38 g, 1.04 mmol), 4-methylmorpholine N-oxide (NMO) (3.41 g, 29.1 mmol), pyridine (1.67 mL, 20.8 mmol), and water (15 mL) to a solution of (cyclopent-3-en-1-yloxy)tris(prop-2-yl)silane (II-B, 5.00 g, from the crude product above) in t-BuOH (50 mL). Stir the reaction mixture at 85 °C for 5 hours. Concentrate the resulting mixture to give a residue, which is then subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 1:1)) to give cis-4-((triisopropylsilyl)oxy)cyclopentane-1,2-diol (II-C, 3.2 g) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ4.54-4.50 (m, 1H), 4.28 (t, J = 4.9Hz, 2H), 2.73 (s, 2H), 2.04-1.99 (m, 2H), 1.95-1.90 (m, 2H), 1.08-1.03 (m, 21H).

[0431] A mixture of cis-4-((triisopropylsilyl)oxy)cyclopentane-1,2-diol (II-C, 2.20 g, 8.01 mmol) and (4-fluorophenyl)boronic acid (0.11 g, 0.80 mmol) in N,N-dimethylformamide (20 mL) was mixed with potassium carbonate (1.66 g, 12.0 mmol) and (bromomethyl)benzene (2.06 g, 12.0 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the residue. The residue was subjected to silica gel column chromatography (eluted with petroleum ether / ethyl acetate (from 1:0 to 10:1)) to give cis-2-(benzyloxy)-4-((triisopropylsilyl)oxy)cyclopentan-1-ol (II-D, 1.70 g, 58%) as a yellow oil. 1H NMR (500MHz, CDCl3) δ7.41-7.30(m,5H),4.63(d,J=11.7Hz,1H),4.60-4.52(m,2H),4.31(q,J=4.7Hz, 1H),4.13-4.10(m,1H),2.16-2.07(m,2H),1.94-1.90(m,1H),1.86-1.81(m,1H),1.08-1.40(m,21H).

[0432] At 0 °C, a solution of cis-2-(benzyloxy)-4-((triisopropylsilyl)oxy)cyclopentan-1-ol (II-D, 1.20 g, 3.29 mmol) in dichloromethane (20 mL) was added to Dysmartin periodane (2.79 g, 6.58 mmol), and the resulting mixture was stirred at room temperature for 5 hours. Afterward, the reaction mixture was quenched with saturated sodium thiosulfate solution (30 mL), diluted with water (50 mL), and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 1:0 to 10:1)) to give 2-(benzyloxy)-4-((triisopropylsilyl)oxy)cyclopentan-1-one (II-E, 1.00 g, 84%). 1 H NMR (500MHz, CDCl3) δ7.48-7.29(m,5H),4.91(d,J=11.7Hz,1H),4.77-4.57(m,2H),4.21(t,J=8.6Hz,1H),2.57-2.52(m,1H),2.39 -2.33(m,2H),2.06-2.00(m,1H),1.10-0.97(m,21H).

[0433] At 0 °C, methyl magnesium bromide (1 M in THF, 12.7 mL, 12.7 mmol) was added dropwise to a solution of 2-(benzyloxy)-4-{[tris(prop-2-yl)silyl]oxy}cyclopentan-1-one (II-E, 2.30 g, 6.34 mmol) in dry THF (20 mL). The mixture was then stirred at room temperature for 1 hour. After completion, the resulting mixture was diluted with saturated ammonium chloride solution (10 mL) and water (20 mL), and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the residue. The residue was subjected to silica gel column chromatography (eluted with petroleum ether / ethyl acetate (from 1:0 to 1:1)) to give 2-(benzyloxy)-1-methyl-4-((triisopropylsilyl)oxy)cyclopentan-1-ol (II-F, 1.50 g, 63%) as a yellow oil.

[0434] A mixture of 2-(benzyloxy)-1-methyl-4-((triisopropylsilyl)oxy)cyclopentan-1-ol (II-F, 1.20 g, 3.17 mmol) and palladium (10% carbon-supported palladium, 0.2 g) in methanol (12 mL) was stirred at room temperature under H2 pressure at one atmosphere. The resulting mixture was filtered, and the filtrate was concentrated to give a residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 0:1)) to give cis-1-methyl-4-((triisopropylsilyl)oxy)cyclopentan-1,2-diol (II-G, 650 mg, 71%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ4.59-4.53(m,1H),4.15-4.13(m,1H),3.85(s,1H),2.41-2. 36(m,1H),1.98-1.95(m,2H),1.87-1.75(m,2H),1.32(s,3H),1.08-1.06(m,21H).

[0435] A mixture of cis-1-methyl-4-((triisopropylsilyl)oxy)cyclopentane-1,2-diol (II-G, 500 mg, 1.73 mmol), (dimethoxymethyl)benzene (395 mg, 2.60 mmol), and pyridine p-toluenesulfonate (PPTS) (10 mg, 0.055 mmol) in dichloromethane (3 mL) was stirred at room temperature for 4 hours. The resulting mixture was concentrated to give a residue, which was then subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 100:1 to 2:1)) to give a yellow oily substance, cis-triisopropyl((3a-methyl-2-phenyltetrahydro-4H-cyclopenta[d][1,3]dioxol-5-yl)oxy)silane (II-H, 350 mg, 54%). 1 H NMR (500MHz, CDCl3) δ7.50-7.48(m,2H),7.42-7.37(m,3H),5.71(s,1H),4.77-4.71(m,1H),4.27(d,J=5.6Hz,1H) ,2.43-2.39(m,1H),2.35-2.30(m,1H),1.77-7.71(m,J=1H),1.57-1.54(m,1H),1.52(s,3H),1.09-1.08(m,21H).

[0436] A mixture of cis-triisopropyl((3a-methyl-2-phenyltetrahydro-4H-cyclopentan[d][1,3]m-dioxacyclopenten-5-yl)oxy)silane (II-H, 350 mg, 0.93 mmol) and tetrabutylammonium fluoride (1 M in THF, 5 mL) was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 1:1)) to give cis-3a-methyl-2-phenyltetrahydro-4H-cyclopentan[d][1,3]m-dioxacyclopenten-5-ol (II-I, 170 mg, 85%) as a yellow oil. 1H NMR (500MHz, CDCl3) δ7.50 (dd, J=6.5, 3.0Hz, 2H), 7.41-7.39 (m, 3H), 5.72 (s, 1H), 4.75-4.69 (m, 1H), 4.30 (d,J=5.7Hz,1H),2.49-2.45(m,1H),2.41-2.37(m,1H),1.75-1.69(m,1H),1.54(s,3H),1.53-1.48(m,1H).

[0437] At 0 °C, a solution of cis-3a-methyl-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopenten-5-ol (II-I, 150 mg, 0.68 mmol) in dichloromethane (4 mL) was added to Dysmartin periodane (347 mg, 0.80 mmol). The mixture was stirred at room temperature for 12 hours. The resulting mixture was filtered. The filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated to give a residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 20:1 to 3:1)) to give cis-3a-methyl-2-phenyltetrahydro-5H-cyclopentane[d][1,3]m-dioxacyclopenten-5-one (II-J, 120 mg, 80%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.49-7.44(m,2H),7.41-7.39(m,3H),5.96(s,1H),4.55(dd,J=5 .0,3.2Hz,1H),2.83-2.79(m,1H),2.75-2.70(m,2H),2.50-2.47(m,1H),1.64(s,3H).

[0438] A mixture of cis-3a-methyl-2-phenyltetrahydro-5H-cyclopentane[d][1,3]m-dioxacyclopenten-5-one (II-J, 380 mg, 1.74 mmol) and bis(2-methoxyethyl)aminothiotrifluoride (BAST) (0.96 mL, 5.22 mmol) in dichloromethane (2 mL) was stirred at room temperature for 48 hours. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to give the residue, and subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 50:1 to 1:1)) to give cis-5,5-difluoro-3a-methyl-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopentenene (II-K, 290 mg, 69%) as a yellow oil. 1H NMR (500MHz, CDCl3) δ7.59-7.54(m,2H),7.46-7.34(m,3H),5.80(s,1H),4.39(d,J=6.6Hz,1 H),2.75-2.65(m,1H),2.62-2.56(m,1H),2.48-2.36(m,1H),2.23-2.15(m,1H),1.57(s,3H).

[0439] A mixture of cis-5,5-difluoro-3a-methyl-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxane-1,2-diol (II-K, 290 mg, 1.20 mmol), palladium (10% carbon-supported palladium, 20 mg), and acetic acid (35 μL, 0.60 mmol) in methanol (10 mL) was stirred at room temperature for 12 hours under H2 at one atmosphere. The resulting mixture was filtered. The filtrate was concentrated to give a residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 0:1)) to give cis-4,4-difluoro-1-methylcyclopentane-1,2-diol (intermediate II, 160 mg, 89%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ4.01-3.93(m,1H),2.57-2.11(m,4H),1.38(s,3H).

[0440] Synthesis of cis-1-methylcyclopentane-4,4-d2-1,2-diol (Intermediate III)

[0441]

[0442] A mixture of cis-4-((triisopropylsilyl)oxy)cyclopentane-1,2-diol (II-C, 6.00 g, 21.9 mmol), (dimethoxymethyl)benzene (4.99 g, 32.8 mmol), and pyridine p-toluenesulfonate (PPTS) (1.10 g, 4.37 mmol) in dichloromethane (60 mL) was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 1:0 to 3:1)) to give cis-triisopropyl((2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopenten-5-yl)oxy)silane (III-A, 8.90 g, crude) as a yellow oil.

[0443] A mixture of cis-triisopropyl((2-phenyltetrahydro-4H-cyclopentan[d][1,3]m-dioxacyclopenten-5-yl)oxy)silane (III-A, 8.00 g, from the crude product described above) and tetrabutylammonium fluoride (TBAF) (1 M in THF, 50.0 mL, 50.0 mmol) was stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 1:1)) to give cis-2-phenyltetrahydro-4H-cyclopentan[d][1,3]m-dioxacyclopenten-5-ol (III-B, 350 mg) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.50-7.48(m,2H),7.42-7.40(m,3H),5.63(s,1H),4.72( dd,J=4.1,1.9Hz,2H),4.70-4.63(m,1H),2.39-2.35(m,2H),1.67-1.62(m,2H).

[0444] At 0 °C, Dysmartin periodane (10.6 g, 25.0 mmol) was added to a mixture of cis-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopenten-5-ol (III-B, 4.30 g, 20.9 mmol) and sodium bicarbonate (5.25 g, 62.6 mmol) in dichloromethane (40 mL). The mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 20:1 to 3:1)) to give cis-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopenten-5-ol (III-C, 3.10 g, 73%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.49-7.46(m,2H),7.44-7.38(m,3H),5.88(s,1H),4.96-4.94(m,2H),2.67-2.63(m,4H).

[0445] Sodium borodeide (1.91 g, 9.79 mmol) was added to a solution of cis-2-phenyl-hexahydrocyclopentane[d][1,3]m-dioxacyclopenten-5-one (III-C, 2.00 g, 9.79 mmol) in methanol (20 mL) at 0 °C. The mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 1:1)) to give cis-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopenten-5-d-5-ol (III-D, 2 g, 98%) as a yellow oil. 1 H NMR(500MHz, CDCl3)δ7.56-7.54(m,2H),7.42-7.41(m,3H),5.74(s,1H),4 .85-4.83(m,2H),2.48-2.43(m,1H),2.35-2.31(m,2H),1.88-1.84(m,2H).

[0446] A mixture of cis-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopenten-5-d-5-ol (III-D, 2.90 g, 15.0 mmol) and 4-dimethylaminopyridine (1.88 g, 15.4 mmol) in pyridine (30 mL) was reacted with p-toluenesulfonyl chloride (4.07 g, 26.6 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 1:1)) to give cis-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopenten-5-yl-5-d-4-methylbenzenesulfonate (III-E, 4.10 g, 81%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.81-7.71(m,2H),7.59-7.52(m,2H),7.40-7.36(m,1H),7.33(dd,J=8.1,6.4Hz,2H),7.30-7.27(m,2H),5.67(s,1H),4. 75(dd,J=4.4,1.7Hz,2H),2.44(s,3H),2.43(d,J=1.2Hz,1H),2.40(d,J=1.5Hz,1H),1.96(dd,J=4.4,1.9Hz,1H),1.92(dd,J=4.5,1.8Hz,1H).

[0447] At 0 °C, lithium aluminum deuteride (460 mg, 11.1 mmol) was added to a solution of cis-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopenten-5-yl-5-d4-methylbenzenesulfonate (III-E, 1.00 g, 2.77 mmol) in THF (10 mL). The mixture was stirred at 50 °C for 12 hours. Sodium sulfate decahydrate was added to the reaction mixture until bubbling ceased, followed by the addition of ethyl acetate (50 mL). The mixture was filtered, and the filtrate was concentrated to give a residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 1:0 to 3:1)) to give cis-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopenten-5,5-d2 (III-F, 443 mg, 83%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.54-7.52(m,2H),7.47-7.33(m,3H),5.64(s,1H),4.71-4.70(m,2H),2.08-2.06(m,2H),1.56-1.47(m,2H).

[0448] A mixture of cis-2-phenyltetrahydro-4H-cyclopentane[d][1,3]m-dioxacyclopentene-5,5-d2 (III-F, 440 mg, 1.22 mmol), palladium (10% carbon-supported palladium, 500 mg), and acetic acid (770 μL, 1.35 mmol) in methanol (20 mL) was stirred at room temperature under H2 pressure at one atmosphere for 12 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give cis-cyclopentane-4,4-d2-1,2-diol (III-G, 580 mg, 82%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ4.08-4.05(m,2H), 1.92-1.85(m,2H), 1.73-1.63(m,2H).

[0449] A mixture of cis-cyclopentane-4,4-d2-1,2-diol (III-G, 190 mg, 1.82 mmol) and (4-fluorophenyl)boronic acid (25 mg, 0.20 mmol) in DMF (2 mL) was supplemented with K2CO3 (378 mg, 2.74 mmol) and (bromomethyl)benzene (468 mg, 2.74 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated to give the residue. The residue was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 1:0 to 3:1)) to give cis-2-(benzyloxy)cyclopentane-4,4-d2-1-ol (III-H, 270 mg, 77%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.41-7.36(m,4H),7.34-7.32(m,1H),4.64(d,J=11.8Hz,1H),4.57(d, J=11.8Hz,1H),4.13-4.10(m,1H),3.86-3.82(m,1H),1.90-1.84(m,1H),1.81-1.73(m,3H).

[0450] At 0 °C, Dysmartin periodane (681 mg, 1.61 mmol) was added to a mixture of cis-2-(benzyloxy)cyclopentan-4,4-d2-1-ol (III-H, 260 mg, 1.34 mmol) and sodium bicarbonate (337 mg, 4.02 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 12 hours. The reaction was diluted with saturated aqueous sodium sulfite solution (20 mL) and water (20 mL). The mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to produce a residue. The residue was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 1:0 to 3:1)) to give 2-(benzyloxy)cyclopentan-1-one-4,4-d2 (III-I, 190 mg, 73%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.42-7.34(m,4H),7.35-7.29(m,1H),4.86(d,J=11.9Hz,1H) ,4.71(d,J=11.9Hz,1H),3.81-3.84(m,1H),2.33-2.21(m,3H),1.87-1.83(m,1H).

[0451] At 0 °C, methyl magnesium bromide (0.66 mL, 1.98 mmol) was added dropwise to a solution of 2-(benzyloxy)cyclopentan-1-one-4,4-d2 (III-I, 190 mg, 0.99 mmol) in tetrahydrofuran (4 mL). The mixture was stirred at 0 °C for 2 hours. The reaction mixture was diluted with saturated ammonium chloride aqueous solution (10 mL) and water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and then concentrated under reduced pressure to give the residue, which was subjected to silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 1:1)) to give cis-2-(benzyloxy)-1-methylcyclopentan-4,4-d2-1-ol (III-J, 70 mg, 34%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.41-7.34(m,4H),7.35-7.30(m,1H),4.68(d,J=11.8Hz,1H),4.54(d,J=11.8H z, 1H), 3.51 (t, J = 6.5Hz, 1H), 1.94-1.90 (m, 1H), 1.84-1.76 (m, 2H), 1.59-1.56 (m, 1H), 1.28 (s, 3H).

[0452] A mixture of cis-2-(benzyloxy)-1-methylcyclopentan-4,4-d2-1-ol (III-J, 70 mg, 0.30 mmol) and palladium (10% carbon-supported palladium, 70 mg) in methanol (5 mL) was stirred at room temperature under H2 pressure at one atmosphere. After completion, the reaction mixture was filtered, and the filtrate was concentrated to give cis-1-methylcyclopentan-4,4-d2-1,2-diol (intermediate III, 30 mg, 75%) as a yellow oil.

[0453] Synthesis of cis-3-methyltetrahydrofuran-3,4-diol (Intermediate IV)

[0454]

[0455] Add potassium osmium tetroxide dihydrate (552 mg, 1.50 mmol), 4-methylmorpholine N-oxide (NMO) (4.80 g, 42.0 mmol), pyridine (2.40 mL, 30.0 mmol), and water (9 mL) to a solution of 2,5-dihydrofuran (IV-A, 2.10 g, 30.0 mmol) in tert-butanol (27 mL). Stir the reaction mixture at 85 °C for 5 hours. After completion, filter the mixture through a Celite pad and quench the filtrate with a saturated aqueous solution of NaHSO3 (10 mL). Concentrate the reaction mixture under reduced pressure and then separate it by silica gel column chromatography (eluting with methanol / dichloromethane (from 0 to 6%)) to provide cis-tetrahydrofuran-3,4-diol (IV-B, 2.55 g, 82%) as a yellow oil.

[0456] Potassium carbonate (K₂CO₃) (3.29 g, 23.8 mmol) was added to a mixture of cis-tetrahydrofuran-3,4-diol (IV-B, 1.65 g, 15.9 mmol) and benzyl bromide (BnBr) (2.85 mL, 23.8 mmol) in N,N-dimethylformamide (DMF) (18 mL), and the reaction mixture was stirred overnight at room temperature. After completion, the reaction was quenched with ice water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was collected, dried over Na₂SO₄, concentrated under reduced pressure, and then subjected to silica gel column chromatography (eluting with ethyl acetate / petroleum ether (from 0%–30%)) to provide cis-4-(benzyloxy)tetrahydrofuran-3-ol (IV-C, 2.26 g, 73%) as a colorless oil.

[0457] At 0 °C, cis-4-(benzyloxy)tetrahydrofuran-3-ol (IV-C, 2.26 g, 11.6 mmol) was carefully added to a solution of dichloromethane (30 mL) with Des Martin periodane (9.86 g, 23.3 mmol). The reaction mixture was stirred overnight at room temperature. After completion, the reaction was quenched by adding saturated sodium thiosulfate solution (20 mL) and saturated sodium carbonate solution (20 mL) at 0 °C, and the mixture was extracted with dichloromethane (100 mL x 2). The organic layer was collected, dried over Na2SO4, concentrated under reduced pressure to give the residue, which was separated by silica gel column chromatography (eluting with ethyl acetate / petroleum ether (from 0 to 20%)) to give 4-(benzyloxy)dihydrofuran-3(2H)-one (IV-D, 1.35 g, 61%) as a colorless oil. 1H NMR (500MHz, DMSO-d6) δ7.41-7.29(m,5H),4.76(d,J=11.7Hz,1H),4.62(d,J=11.7Hz,1H),4.35-4.28 (m,1H),4.20(t,J=7.1Hz,1H),4.07-4.00(m,1H),3.96(d,J=17.4Hz,1H),3.82(dd,J=9.6,7.1Hz,1H).

[0458] At -20°C under N2 protection, methyl magnesium bromide (1M in THF, 11.7 mL) was added to a solution of 4-(benzyloxy)dihydrofuran-3(2H)-one (IV-D, 1.12 g, 5.80 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at 0°C for 1 hour. After completion, a saturated NH4Cl solution (10 mL) was added at 0°C to quench the reaction. The mixture was extracted with ethyl acetate (100 mL x 2). The organic layer was collected, dried over Na2SO4, concentrated under reduced pressure, and then separated by silica gel column chromatography to provide cis-4-(benzyloxy)-3-methyltetrahydrofuran-3-ol (IV-E, 321 mg, 23%) as a colorless oil. 1 H NMR (500MHz, DMSO-d6) δ7.40-7.32(m,4H),7.32-7.26(m,1H),4.69(d,J=12.1Hz,1H),4.61(s,1H),4.55(d,J= 12.2Hz,1H),3.96-3.87(m,1H),3.67-3.58(m,2H),3.54(d,J=8.3Hz,1H),3.45(d,J=8.3Hz,1H),1.22(s,3H).

[0459] Palladium (10% carbon-supported palladium, 100 mg) and acetic acid (1 drop) were added to a solution of cis-4-(benzyloxy)-3-methyltetrahydrofuran-3-ol (IV-E, 321 mg, 1.54 mmol) in methanol (20 mL). The reaction mixture was stirred overnight under H2 at one atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide cis-3-methyltetrahydrofuran-3,4-diol (intermediate IV, 158 mg, 87%) as a colorless oil.

[0460] Synthesis of cis-tetrahydro-2H-pyran-3,4-diol (intermediate V)

[0461]

[0462] Add potassium osmium tetroxide (22 mg, 0.06 mmol), 4-methylmorpholine N-oxide (NMO) (195 mg, 1.67 mmol), pyridine (96 μL, 1.20 mmol), and water (1.5 mL) to a solution of (cyclopent-3-en-1-yloxy)tris(prop-2-yl)silane (VA, 1.50 g, 6.24 mmol) in tert-butanol (5 mL). Stir the reaction mixture at 85 °C for 5 hours. Concentrate the reaction mixture to give the residue, which is then separated by silica gel column chromatography (eluting with methanol / dichloromethane (from 0 to 10%)) to give cis-tetrahydro-2H-pyran-3,4-diol (intermediate V, 1.30 g, 76%) as a yellow oil.

[0463] 1 H NMR (500MHz, CDCl3) δ3.89-3.82(m,3H),3.78-3.76(m,1H),3.56-3.52(m, 1H),3.48-3.43(m,1H),3.03(s,2H),1.90-1.83(m,1H),1.80-1.75(m,1H).

[0464] Synthesis of cis-5,5-difluoro-1-methylcyclohexane-1,2-diol (intermediate VI)

[0465]

[0466] At 0 °C, (2-methylallyl)magnesium bromide (0.5 M in THF, 286 mL, 143 mmol) was added to a solution of pent-4-enal (VI-A, 10.0 g, 119 mmol) in THF (100 mL). The reaction mixture was stirred at 25 °C under a N2 atmosphere for 1 hour. After completion, the reaction mixture was quenched with H2O (200 mL) at 0 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to provide 2-methyloct-1,7-dien-4-ol (VI-B, 16.2 g, 97%) as a colorless oil.

[0467] To a solution of 2-methyloctyl-1,7-dien-4-ol (VI-B, 16.2 g, 116 mmol) in dichloromethane (500 mL), tert-butyldiphenylchlorosilane (TBDPSCl) (47.6 g, 173 mmol) and N,N-dimethylpyridin-4-amine (DMAP) (28.2 g, 231 mmol) were added, and the reaction mixture was stirred overnight at room temperature. Afterward, the reaction mixture was diluted with H₂O (300 mL) and extracted with dichloromethane (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, and concentrated under reduced pressure to produce a residue. The residue was separated by silica gel column chromatography to provide tert-butyl[(2-methyloctyl-1,7-dien-4-yl)oxy]diphenylsilane (VI-C, 39.1 g, 89%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.61-7.0(m,4H),7.30-7.26(m,6H),5.60-5.53(m,1H),4.82-4.75(m,2H),4.56-4.51( m,2H),3.79-3.16(m,1H),2.08-2.04(m,2H),2.04-1.98(m,2H),1.40-1.35(m,2H),1.32(s,3H),0.97(s,9H).

[0468] Grubbs catalyst II (4.38 g, 5.16 mmol) was added to a solution of tert-butyl[(2-methyloct-1,7-dien-4-yl)oxy]diphenylsilane (VI-C, 39.1 g, 103 mmol) in dichloromethane (500 mL). The reaction mixture was stirred overnight at 40 °C under a nitrogen atmosphere. After completion, the reaction mixture was diluted with H2O (100 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography to provide tert-butyl[(3-methylcyclohexyl-3-en-1-yl)oxy]diphenylsilane (VI-D, 32.1 g, 89%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.70-7.67(m,4H),7.42-7.35(m,6H),5.29(s,1H),3.96-3.94(m,1H) ,2.12-2.03(m,3H),1.86-1.85(m,1H),1.66-1.61(m,1H),1.58-1.52(m,4H),1.07(s,9H).

[0469] Potassium osmium tetroxide dihydrate (1.68 g, 4.56 mmol) and 4-methylmorpholine N-oxide (NMO) (12.9 g, 110 mmol) were added to a solution of tert-butyl[(3-methylcyclohexyl-3-en-1-yl)oxy]diphenylsilane (VI-D, 32.1 g, 91.4 mmol) in THF (300 mL) and H2O (30 mL), and the reaction mixture was stirred overnight at 25 °C. After completion, the reaction mixture was quenched with saturated NaHSO3 solution (50 mL) and H2O (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to produce a residue, which was separated by silica gel column chromatography to give cis-5-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexane-1,2-diol (VI-E, 30.3 g, 86%) as a colorless oil.

[0470] A mixture of cis-5-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexane-1,2-diol (VI-E, 30.3 g, 78.8 mmol) and (dimethoxymethyl)benzene (24.0 g, 157 mmol) in dichloromethane (300 mL) was mixed with pyridine p-toluenesulfonate (PPTS) (3.96 g, 15.8 mmol), and the reaction mixture was stirred overnight at 25 °C. Afterward, the reaction mixture was diluted with H₂O (100 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure to produce a residue. The residue was separated by silica gel column chromatography to provide cis-tert-butyl((3a-methyl-2-phenylhexahydrobenzo[d][1,3]m-dioxacyclopenten-5-yl)oxy)diphenylsilane (VI-F, 25.2 g, 67%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.66-7.65(m,4H),7.43-7.26(m,11H),5.93-5.89(m,1H),4.21-4.14(m,1H),3.95-3.90(m, 1H),2.16-2.10(m,1H),1.95-1.92(m,1H),1.85-1.76(m,2H),1.62-1.55(m,4H),1.38-1.36(m,1H),1.08(s,9H).

[0471] A solution of cis-tert-butyl((3a-methyl-2-phenylhexahydro-2H-1,3-benzo[d][1,3]m-dioxacyclopenten-5-yl)oxy)diphenylsilane (VI-F, 25.2 g, 53.3 mmol) in THF (300 mL) was mixed with tetrabutylammonium fluoride (TBAF) (20.9 g, 80.0 mmol), and the reaction mixture was stirred at 70 °C for 2 hours. After completion, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (120 mL x 3). The combined organic layers were washed with brine (100 mL x 5), dried over Na2SO4, and concentrated under reduced pressure to produce a residue, which was subjected to silica gel column chromatography to provide cis-3a-methyl-2-phenyl-hexahydro-2H-1,3-benzo[d][1,3]m-dioxacyclopenten-5-ol (VI-G, 12.1 g, 97%) as a colorless oil.

[0472] Sodium bicarbonate (8.68 g, 103 mmol) and Dys-Martin reagent (32.9 g, 77.5 mmol) were added to a solution of cis-3a-methyl-2-phenyl-hexahydro-2H-1,3-benzodioxane-5-ol (VI-G, 12.1 g, 51.6 mmol) in dichloromethane (200 mL) at 0 °C. The reaction mixture was stirred at room temperature under N2 for 2 hours. After stirring, the reaction mixture was quenched with a saturated solution of Na2S2O3 (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography to provide cis-3a-methyl-2-phenyltetrahydrobenzo[d][1,3]m-dioxane-5(4H)-one (VI-H, 10.4 g, 87%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.42-7.37(m,5H),5.80(s,1H),4.26(s,1H),2.79-2.75 (m,1H),2.60-2.42(m,2H),2.28-2.24(m,2H),2.03-1.95(m,1H),1.48(s,3H).

[0473] At 0 °C, diethylaminosulfur trifluoride (DAST) (20 mL) was added to a solution of cis-3a-methyl-2-phenyltetrahydrobenzo[d][1,3]m-dioxacyclopenten-5(4H)-one (VI-H, 5.00 g, 21.5 mmol) in dichloromethane (20 mL). The reaction mixture was stirred overnight at room temperature under N2. After completion, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to produce a residue, which was separated by silica gel column chromatography to provide cis-5,5-difluoro-3a-methyl-2-phenylhexahydrobenzo[d][1,3]m-dioxacyclopentenene (VI-I, 3.50 g, 64%) as a colorless oil.

[0474] Palladium (10% carbon-supported palladium, 500 mg) was added to a solution of cis-5,5-difluoro-3a-methyl-2-phenylhexahydrobenzo[d][1,3]m-dioxane (VI-I, 3.50 g, 13.8 mmol) in ethyl acetate (100 mL), and the reaction mixture was stirred overnight at room temperature under H2 (1 atm). After completion, the mixture was passed through a small piece of [unclear - likely a typo, should be 1 atm]. The mixture was filtered and the filtrate was concentrated under reduced pressure to produce a residue. The residue was separated by silica gel column chromatography to provide cis-5,5-difluoro-1-methylcyclohexane-1,2-diol (intermediate VI, 1.80 g, 79%) as a white solid. 1 HNMR (400MHz, DMSO-d6) δ4.62-4.61(m,1H),4.23(s,1H),3.37-3.36(m,1H),2.02-1.98(m,1H),1.85-1.73(m,4H),1.59-1.57(m,1H),1.11(s,3H). 19 F NMR(400MHz, DMSO-d6)δ-86.9&-87.6(d),-89.3&-89.9(d).

[0475] Synthesis of oxepane-4,5-diol (intermediate VII)

[0476]

[0477] At -30 °C, after 15 min, ethyl diazonyl ether (1.62 mL, 15.4 mmol) and boron trifluoride ether (1.80 mL, 15.3 mmol) were added to a solution of oxan-4-one (VII-A, 1.53 g, 15.3 mmol) in THF (10 mL). The reaction was stirred at this temperature for 1 h. It was then slowly quenched with a 30% aqueous solution of Na₂CO₃. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 1:0 to 5:1)) to provide ethyl 5-oxoxetane-4-carboxylate (VII-B, 1.36 g, 48%) as a colorless oil. LC-MS (ESI): m / z 187.1 [M+H] + .

[0478] At 0 °C, Raney nickel (430 mg, 1.99 mmol) was added to a solution of ethyl 5-oxoxetane-4-carboxylate (VII-B, 3.70 g, 19.9 mmol) in EtOH (25 mL). The resulting mixture was stirred at 50 °C for 12 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to produce a residue. The residue was subjected to silica gel column chromatography to give ethyl 5-hydroxyoxetane-4-carboxylate (VII-C, 3.40 g, 91%) as a colorless oil. LC-MS (ESI): m / z 189.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ4.31-4.29(m,1H),4.20(q,J=7.0Hz,2H),3.89-3.84(m,1H),3.80-3.71(m,2H),3.68-3.64(m,1H),3.13(br s,1H),2.81-2.78(m,1H),2.47-2.40(m,1H),2.00-1.95(m,1H),1.91-1.80(m,2H),1.30(t,J=7.0Hz,3H).

[0479] At 0 °C, triethylamine (3.0 mL) and methanesulfonyl chloride (2.0 mL, 22.5 mmol) were added to a solution of ethyl 5-hydroxyoxetane-4-carboxylate (VII-C, 2.82 g, 15.0 mmol) in anhydrous dichloromethane (30 mL). The mixture was stirred at room temperature for 5 hours. The reaction was quenched with saturated NaHCO3 solution (50 mL) and extracted with dichloromethane (100 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give ethyl 5-((methanesulfonyl)oxy)oxetane-4-carboxylate (VII-D, 3.67 g, 92%) as a colorless oil. LC-MS (ESI): m / z 267.1 [M+H] + .

[0480] At room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.0 mL) was added to a solution of ethyl 5-((methanesulfonyl)oxy)oxetane-4-carboxylate (VII-D, 3.87 g, 14.5 mmol) in THF (30 mL). The reaction mixture was stirred for 4 hours, then diluted with EtOAc (50 mL) and washed with brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to provide ethyl 2,3,6,7-tetrahydrodihydrooxane as a colorless oil. ethyl 2,3,6,7-tetrahydrooxepine-4-carboxylate (VII-E, 1.27 g, 51%). 1 H NMR (500 MHz, CDCl3) δ7.22 (t, J = 6.0 Hz, 1H), 4.21 (q, J = 7.0 Hz, 2H), 3.72-3.70 (m, 4H), 2.78-2.75 (m, 2H), 2.52-2.49 (m, 2H), 1.31 (t, J = 6.0 Hz, 3H).

[0481] 2,3,6,7-Tetrahydrodihydrooxygenase A mixture of ethyl 4-carboxylate (VII-E, 1.07 g, 6.29 mmol), potassium osmium tetroxide dihydrate (120 mg, 0.37 mmol), 4-methylmorpholine N-oxide (NMO) (1.20 g, 10.3 mmol), pyridine (0.8 mL), H₂O (7 mL), and t-BuOH (20 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. Afterward, the mixture was cooled to room temperature, filtered through a Celite pad, and the pad was washed with methanol (HPLC grade, 30 mL). The filtrate was concentrated under reduced pressure to give the residue, which was then separated by silica gel column chromatography to give cis-4,5-dihydroxyoxetane-4-carboxylate (VII-F, 1.01 g, 78%). 1 H NMR(500MHz, CDCl3)δ4.32(q,J=7.0Hz,2H),4.20(d,J=10Hz,1H),3.84-3.80(m,2H),3.78-3.71(m,2H),3.5 6(s,1H),2.45-2.39(m,1H),2.20-2.5(m,2H),1.85-1.81(m,1H),1.75-1.71(m,1H),1.34(t,J=7.0Hz,3H).

[0482] At 0 °C, tert-butyldimethylchlorosilane (TBDMSCl) (1.26 g, 8.38 mmol) was added to a mixture of cis-4,5-dihydroxyoxetane-4-carboxylic acid ethyl ester (VII-F, 710 mg, 3.50 mmol), imidazole (790 mg, 11.6 mmol), and triethylamine (1.2 mL) in dichloromethane (30 mL). The reaction mixture was heated to 80 °C and stirred at 80 °C for 12 hours, then quenched with saturated NaHCO3 solution (50 mL) and extracted with dichloromethane (60 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 5-[(tert-butyldimethylsilyl)oxy]-4-hydroxyoxetane-4-carboxylic acid ethyl ester (VII-G, 0.74 g, 68%). 1 H NMR (500MHz, CDCl3) δ4.27 (q, J = 7.0Hz, 2H), 4.16-4.09 (m, 1H), 3.84-3.78 (m, 2H), 3.74-3.68 (m, 2H), 3.33 (brs, 1H), 2.52-2.4 4(m,1H),2.20-2.15(m,1H),1.79-1.75(m,1H),1.65-1.61(m,1H),1.32(t,J=7.0Hz,3H)0.86(s,9H),0.08(s,3H),0.01(s,3H).

[0483] At 0 °C, NaBH4 (560 mg, 16.7 mmol) was added to a mixture of cis-5-[(tert-butyldimethylsilyl)oxy]-4-hydroxyoxetane-4-carboxylic acid ethyl ester (VII-G, 1.33 g, 4.20 mmol) and CaCl2 (930 mg, 8.40 mmol) in THF (12 mL). The mixture was stirred for 15 min, then slowly heated to room temperature and stirred for 12 h. The reaction was quenched with saturated NaHCO3 solution (10 mL) and extracted with dichloromethane (60 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to produce a residue, which was separated by silica gel column chromatography to give 5-[(tert-butyldimethylsilyl)oxy]-4-(hydroxymethyl)oxetane-4-ol (VII-H, 1.12 g, 97%). LC-MS(ESI): m / z 277.2 [M+H] + .

[0484] To a solution of 5-[(tert-butyldimethylsilyl)oxy]-4-(hydroxymethyl)oxetane-4-ol (VII-H, 64 mg, 0.23 mmol) in acetonitrile (1 mL) and H₂O (0.1 mL), NaIO₄ (50 mg, 0.23 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Then, ethyl acetate (15 mL) and a saturated aqueous solution of Na₂SO₃ (8 mL) were added. The mixture was stirred vigorously for 15 min, and the two phases were separated using a separatory funnel. The aqueous solution was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 5-[(tert-butyldimethylsilyl)oxy]oxetane-4-one (VII-I, 46 mg, 81%). 1 H NMR (500MHz, CDCl3) δ4.39 (dd, J=7.0, 2.0Hz, 1H), 4.10-4.05 (m, 1H), 3.99-3.95 (m, 1H), 3.92-3.89 (m, 2H ),2.85-2.80(m,1H),2.72-2.66(m,1H),1.91-1.84(m,1H),1.80-1.74(m,1H),0.95(s,9H),0.11(s,6H).

[0485] At 0 °C, DIBAL-H (1 M in hexane, 1.04 mL, 1.04 mmol) was added to a solution of 5-[(tert-butyldimethylsilyl)oxy]oxetane-4-one (VII-I, 85 mg, 0.35 mmol) in THF (1 mL). The mixture was heated to room temperature and stirred for 2 hours. The resulting solution was filtered through a Celite filter, washed with dichloromethane (20 mL), and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 5-((tert-butyldimethylsilyl)oxy)oxetane-4-ol (VII-J, 75 mg, 87%). 1 H NMR (500MHz, CDCl3) δ3.85-3.80(m,1H),3.78-3.72(m,1H),3.71-3.62(m,4H),2.10-2. 01(m,1H),1.97-1.91(m,1H),1.83-1.74(m,2H),0.92(s,9H),0.12(s,3H),0.11(s,3H).

[0486] At 0 °C, TBAF (1 M in THF, 90 μL, 0.09 mmol) was added to a solution of 5-[(tert-butyldimethylsilyl)oxy]oxetane-4-ol (VII-J, 23 mg, 0.09 mmol) in dry THF (1 mL), and the resulting solution was stirred for 45 min, then the mixture was heated to room temperature. The resulting solution was diluted with dichloromethane (20 mL) and quenched with water (5 mL). The organic layer was washed with brine (5 mL), dried over NaSO4, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to give oxetane-4,5-diol (intermediate VII, 12 mg, 90%) as a mixture of isomers. LC-MS (ESI): m / z 133.1 [M+H] + .

[0487] Synthesis of cis-oxacycloheptan-3,4-diol (intermediate VIII)

[0488]

[0489] Under a nitrogen atmosphere, oxane-4-one (VIII-A, 20.0 g, 200 mmol) and potassium hydroxide (22.4 g, 400 mmol) were dissolved in methanol (320 mL). The resulting solution was cooled to 0 °C, and a solution of iodine (45.6 g, 180 mmol) in methanol (320 mL) was added dropwise over 2 hours. Subsequently, the reaction mixture was heated to room temperature and stirred for 1 hour. The solvent was then removed under reduced pressure, and the residue was suspended in ethyl acetate (500 mL). After filtration, the filtrate was concentrated to give a crude product, which was separated by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 0:1)) to give a yellow oily substance, 4,4-dimethoxytetrahydro-2H-pyran-3-ol (VIII-B, 13.4 g, 41%). 1 H NMR (500MHz, CDCl3) δ3.85 -3.78(m,2H),3.73-3.66(m,2H),3.52-3.47(m,1H),3.28(s,3H),3.26(s,3H),1.98-1.92(m,1H),1.79-1.75(m,1H).

[0490] Sodium hydride (0.87 g, 21.6 mmol) was added to a solution of 4,4-dimethoxytetrahydro-2H-pyran-3-ol (VIII-B, 2.70 g, 16.7 mmol) in tetrahydrofuran (50 mL) at 0 °C. (Bromomethyl)benzene (2.38 mL, 20.0 mmol) was added dropwise to the mixture, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was then quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were concentrated to give the residue, which was separated by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 20:1 to 1:1)) to give 3-(benzyloxy)-4,4-dimethoxytetrahydro-2H-pyran (VIII-C, 4.20 g, 100%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.42-7.28(m,5H),4.77(d,J=12.1Hz,1H),4.64(d,J=12.1Hz,1H),3.99(dd,J=12.3,3.0Hz,1H),3.85-3.81 (m,1H),3.63-3.60(m,1H),3.56-3.51(m,1H),3.44-3.42(m,1H),3.24(s,3H),3.22(s,3H),2.12-2.07(m,1H),1.79-1.75(m,1H).

[0491] Hydrochloric acid (2M solution, 41.6 mL) was added to a solution of 3-(benzyloxy)-4,4-dimethoxytetrahydro-2H-pyran (VIII-C, 4.20 g, 16.7 mmol) in tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 12 hours. The resulting mixture was adjusted to pH 7 with saturated sodium carbonate and extracted with ethyl acetate (50 mL x 3). The combined organic layers were concentrated to give the residue, which was separated by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 50:1 to 1:1)) to give 3-(benzyloxy)tetrahydro-4H-pyran-4-one (VIII-D, 2.90 g, 84%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.40-7.30(m,5H),4.87(d,J=11.9Hz,1H),4.56(d,J=11.9Hz,1H),4.21-4.17(m ,1H),4.17-4.07(m,1H),4.02-3.99(m,1H),3.76-3.71(m,1H),3.62-3.58(m,1H),2.62-2.60(m,2H).

[0492] At -78 °C, a solution of 3-(benzyloxy)tetrahydro-4H-pyran-4-one (VIII-D, 2.30 g, 11.2 mmol) in dichloromethane (40 mL) was added to a solution of BF3-ethyl ether complex (5.6 mL, 44.6 mmol) and (trimethylsilyl)diazomethane solution (2 M in hexane, 16.7 mL, 33.5 mmol). The reaction mixture was stirred at -78 °C for 1 h, quenched with saturated sodium bicarbonate solution (2.6 mL) and water (20 mL), and extracted with dichloromethane (20 mL x 3). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to produce a residue. The residue was redissolved in methanol (4 mL), and pyridine-1-onium 4-methylbenzenesulfonate (4.20 g, 16.7 mmol) was added to the resulting solution. After stirring at 25°C for 1 hour, the reaction mixture was concentrated under reduced pressure, followed by the addition of water (50 mL) and extraction with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to produce a residue. The residue was separated by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 20:1 to 0:1)) to give a yellow oily 3-(benzyloxy)oxetane-4-one (VIII-E, 390 mg, 16%). 1H NMR (500MHz, CDCl3) δ7.42-7.32(m,5H),4.74(d,J=11.8Hz,1H),4.52(d,J=11.8Hz,1H),4.12(t,J=5.1Hz,1H),3 .96-3.93(m,1H),3.85-3.78(m,3H),2.79-2.73(m,1H),2.57-2.48(m,1H),2.03-1.92(m,1H),1.91-1.81(m,1H).

[0493] Sodium borohydride (430 mg, 12.7 mmol) was added to a solution of 3-(benzyloxy)oxetane-4-one (VIII-E, 1.40 g, 6.36 mmol) in methanol (20 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give a residue, which was separated by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 1:1)) to give cis-3-(benzyloxy)oxetane-4-ol (VIII-F, 660 mg, 47%) as a yellow oil. 1 H NMR(500MHz, CDCl3)δ7.41-7.30(m,5H),4.69-4.58(m,2H),4.13-4.08(m,1H),3.79-3.66(m,4H), 3.59-3.61(m,1H),2.52(d,J=4.3Hz,1H),2.11-2.01(m,2H),1.74-1.70(m,1H),1.62-1.56(m,1H).

[0494] Palladium (10% carbon-supported palladium, 335 mg) was added to a solution of cis-3-(benzyloxy)oxetane-4-ol (VIII-F, 700 mg, 3.15 mmol) in methanol (2 mL), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 0:1)) to give cis-oxetane-3,4-diol (intermediate VIII, 320 mg, 77%) as a yellow oil. 1 H NMR(500MHz, CDCl3)δ3.85(s,1H),3.79-3.73(m,4H),3.63-3.60(m,1H),2.71-2.70 (m,1H),2.70-2.56(m,1H),1.91-1.84(m,2H),1.80-1.74(m,1H),1.70-1.63(m,1H).

[0495] Synthesis of cis-3-fluoro-1-(methanesulfonyl)piperidine-4-amine (intermediate IX)

[0496]

[0497] At 0 °C, methanesulfonyl chloride (298 mg, 2.60 mmol) was added to a mixture of cis-tert-butyl(3-fluoropiperidin-4-yl)carbamate (IX-A, 480 mg, 2.20 mmol) and triethylamine (667 mg, 6.60 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature under N2 for 1 hour. The reaction mixture was diluted with H2O (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography to provide cis-tert-butyl(3-fluoro-1-(methylsulfonyl)piperidin-4-yl)carbamate (IX-B, 603 mg, 93%) as a white solid. LC-MS (ESI): m / z 297.1 [M+H] + .

[0498] At 0 °C, trifluoroacetic acid (0.6 mL) was added to a solution of cis-tert-butyl(3-fluoro-1-(methanesulfonyl)piperidin-4-yl)carbamate (IX-B, 603 mg, 2.00 mmol) in dichloromethane (6 mL). The reaction mixture was stirred overnight at room temperature under N2. After completion, the reaction mixture was concentrated under reduced pressure to give cis-3-fluoro-1-(methanesulfonyl)piperidin-4-amine as a TFA salt (intermediate IX, 380 mg, 61%). LC-MS (ESI): m / z 197.1 [M+H] + .

[0499] Synthesis of 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-amine (intermediate X)

[0500]

[0501] At 0 °C, 1-methyl-1H-pyrazole-4-sulfonyl chloride (XA, 1.00 g, 5.50 mmol) was added to a mixture of tert-butyl N-(piperidin-4-yl)carbamate (1.11 g, 5.50 mmol) and triethylamine (2.3 mL, 16.5 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After completion, the mixture was diluted with H2O (40 mL) and extracted with dichloromethane (40 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to provide tert-butyl(1-((1-methyl-1H-pyrazole-4-yl)sulfonyl)piperidin-4-yl)carbamate (XB, 1.70 g, 89%) as a white solid. LC-MS (ESI): m / z 345.1 [M+H] + .

[0502] At 0 °C, HCl (4 M in dioxane, 20 mL) was added to a solution of tert-butyl(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)carbamate (XB, 1.70 g, 4.94 mmol) in dioxane (20 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to provide 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine (intermediate X, 1.10 g, 80%) as an HCl salt. LC-MS (ESI): m / z 245.1 [M+H] + .

[0503] Synthesis of 4-amino-N-(oxetane-3-yl)benzenesulfonamide (intermediate XI)

[0504]

[0505] Oxycyclobutane-3-amine (XI-A, 0.10 mL, 1.35 mmol) and triethylamine (0.60 mL, 4.06 mmol) were added to a solution of 4-nitrobenzenesulfonyl chloride (300 mg, 1.35 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was then poured into ice water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 4-nitro-N-(oxycyclobutane-3-yl)benzenesulfonamide (XI-B, 250 mg, 72%) as a white solid. LC-MS (ESI): m / z 259.0 [M+H] + .

[0506] NH4Cl (1026 mg, 19.4 mmol) was added to a mixture of 4-nitro-N-(oxetane-3-yl)benzenesulfonamide (XI-B, 250 mg, 0.97 mmol) and iron powder (65 mg, 9.68 mmol) in EtOH (7 mL) and H2O (3 mL), and the reaction mixture was stirred overnight at 60 °C. The reaction mixture was then passed through a small piece of... The solution was filtered through a filter pad, and the filter cake was washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give 4-amino-N-(oxetane-3-yl)benzenesulfonamide (intermediate XI, 200 mg, 91%) as a brown solid. LC-MS (ESI): m / z 229.1 [M+H] + .

[0507] Synthesis of 4-amino-3-fluoro-N-(methyl-d3)benzenesulfonamide (intermediate XII)

[0508]

[0509] 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (XII-A, 900 mg, 3.76 mmol) was added to a mixture of deuterated methylamine hydrochloride (397 mg, 5.63 mmol) and potassium carbonate (1.56 g, 11.3 mmol) in dichloromethane / water (15 mL / 5 mL). The mixture was stirred at room temperature for 2 hours, then diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine and concentrated under reduced pressure to give 3-fluoro-N-(methyl-d3)-4-nitrobenzenesulfonamide (XII-B, 1.00 g, crude) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ8.22 (dd, J=8.8, 6.9Hz, 1H), 7.95-7.61 (m, 2H), 4.70 (s, 1H).

[0510] A mixture of 3-fluoro-N-(methyl-d3)-4-nitrobenzenesulfonamide (XII-B, 1.00 g, from the crude product of the previous step) and palladium (10% carbon-supported palladium, 0.45 g) in methanol (15 mL) was stirred at room temperature under H2 at one atmosphere for 12 hours. The reaction mixture was then filtered, and the filtrate was concentrated to give a residue, which was separated by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 10:1 to 1:1)) to give 4-amino-3-fluoro-N-(methyl-d3)benzenesulfonamide (intermediate XII, 480 mg) as a yellow solid. 1H NMR (500MHz, CDCl3) δ7.54-7.43 (m, 2H), 6.84 (t, J = 8.3Hz, 1H), 4.22 (s, 3H).

[0511] Synthesis of 4-amino-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (intermediate XIII)

[0512]

[0513] Triethylamine (1.38 mL, 10.0 mmol) was added to a mixture of tetrahydro-2H-pyran-4-amine (XIII-A, 505 mg, 5.00 mmol) and 4-nitrobenzenesulfonyl chloride (1.10 g, 5.00 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give 4-nitro-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (XIII-B, crude), which could be used for the next step without further purification.

[0514] Palladium (10% carbon-supported palladium, 200 mg) was added to a solution of 4-nitro-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (XIII-B, from the crude product of the previous step) in methanol (20 mL). The mixture was stirred overnight at room temperature under H2 at one atmosphere. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give 4-amino-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (intermediate XIII, 1.04 g, 82% from XIII-A). LC-MS (ESI): m / z 257.1 [M+H] + .

[0515] Synthesis of 4-amino-N-(3-methyloxetane-3-yl)benzenesulfonamide (intermediate XIV)

[0516]

[0517] 4-nitrobenzene-1-sulfonyl chloride (0.75 g, 3.37 mmol) was added to a mixture of 3-methyloxetane-3-amine HCl salt (XIV-A, 0.41 g, 3.28 mmol) and triethylamine (1.4 mL, 10.1 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature for 3 hours, then poured into water (200 mL) and filtered. The filter cake was washed with dichloromethane (30 mL). The filtrate was then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give N-(3-methyloxetane-3-yl)-4-nitrobenzenesulfonamide (XIV-B, 0.89 g, 99%). LC-MS (ESI): m / z 271.0 [MH] -.

[0518] Palladium (10% carbon-supported palladium, 0.32 g) was added to a solution of N-(3-methyloxetane-3-yl)-4-nitrobenzene-1-sulfonamide (XIV-B, 0.89 g, 3.27 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was then passed through a small piece of [material / material]. Filter the filter cake with EtOAc (30 mL) and concentrate the filtrate under reduced pressure. Separate the resulting residue by silica gel column chromatography to give 4-amino-N-(3-methyloxetane-3-yl)benzene-1-sulfonamide (intermediate XIV, 0.45 g, 57%).

[0519] 1 H NMR(500MHz,DMSO-d6)δ7.79(s,1H),7.89(d,J=8.5Hz,2H),6.62(d,J=8.5Hz ,2H),5.97(s,2H),4.92(d,J=6.0Hz,2H),4.04(d,J=6.0Hz,2H),1.43(s,3H).

[0520] Diagram 1. Synthesis of 4-((5-cyano-4-(cyclopentylmethoxy)pyrimidin-2-yl)amino)benzenesulfonamide (1)

[0521]

[0522] At 0 °C, N,N-diisopropylethylamine (DIEA) (4.46 g, 34.5 mmol) was added to a mixture of 2,4-dichloropyrimidin-5-carboxynitrile (1A, 2.00 g, 11.5 mmol) and 4-aminobenzene-1-sulfonamide (2.18 g, 12.7 mmol) in anhydrous N,N-dimethylformamide (DMF) (20 mL). The reaction mixture was stirred at room temperature for 10 minutes and then poured into water (200 mL). The formed precipitate was filtered, washed with water (30 mL x 2), and dried to give 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)benzenesulfonamide (1B, 1.60 g, 45%) as a yellow solid. LC-MS (ESI): m / z 310.0 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ11.15(s,1H),8.98(s,1H),7.90-7.76(m,4H),7.29(s,2H).

[0523] A solution of 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)benzenesulfonamide (1B, 60 mg, 0.19 mmol) and cyclopentylmethanol (58 mg, 0.58 mmol) in dimethyl sulfoxide (DMSO) (3 mL) was mixed with potassium tert-butoxide (t-BuOK) (65 mg, 0.58 mmol), and the reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was then poured into a cold saturated solution of NH4Cl (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to produce a residue. The residue was separated by preparative HPLC to give 4-((5-cyano-4-(cyclopentylmethoxy)pyrimidin-2-yl)amino)benzenesulfonamide (1, 16 mg, 23%). LC-MS (ESI): m / z 374.1 [M+H] + .

[0524] 1 H NMR(400MHz,DMSO-d6)δ10.65(br s,1H),8.75(s,1H),7.90(d,J=8.8Hz,2H),7.79(d,J=8.8Hz,2H),7.26(s,2H),4.39(d,J =7.2Hz,2H),2.45-2.39(m,1H),1.79-1.77(m,2H),1.65-1.55(m,4H),1.36-1.26(m,2H).

[0525] Diagram 2. Synthesis of cis-4-((5-cyano-4-((2-hydroxycyclohexyl)oxy)pyrimidin-2-yl)amino)benzenesulfonamide (2)

[0526]

[0527] t-BuOK (152 mg, 1.36 mmol) and cis-cyclohexane-1,2-diol (158 mg, 1.36 mmol) were added to a solution of 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (1B, 140 mg, 0.45 mmol) in DMSO (3 mL), and the reaction mixture was stirred at 90 °C for 1 hour. After completion, the mixture was poured into ice-cooled saturated NH4Cl solution (15 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to produce a residue, which was separated by silica gel column chromatography to give cis-4-((4-((2-hydroxycyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (2) in racemic form, which was further separated by chiral SFC to give:

[0528] Enantiomer 1 (2a, 97.9% ee); retention time: 3.93 min. LC-MS (ESI): m / z 390.1 [M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ10.60(s,1H),8.73(s,1H),7.86(d,J=9.0Hz,2H),7.77(d,J=8.9Hz,2H),7.26(s,2 H), 5.33 (s, 1H), 4.85 (d, J = 4.7Hz, 1H), 3.90 (s, 1H), 1.95 (d, J = 4.1Hz, 1H), 1.75-1.53 ​​(m, 5H), 1.34 (m, 2H).

[0529] Enantiomer 2 (2b, 99% ee); Retention time: 4.76 min; LC-MS (ESI): m / z 390.0 [M+H] + .

[0530] Analytical methods: Column: ChiralCel OD, 250×4.6mm ID, 5μm; Mobile phase: A, CO2, and B, MeOH (0.05% DEA); Gradient: 8min@B 40%; Flow rate: 2.0mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0531] SFC method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralCel OD, 250×21.2mm I.D., 5μm; Mobile phase: A, CO2, and B, MeOH + 0.1% NH3·H2O; Gradient: B 40%; Flow rate: 50mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0532] Figure 3. Cis-4-((2-hydroxy-2-methylcyclopentyl)oxy)-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidine

[0533] Synthesis of 5-formonitrile(3)

[0534]

[0535] To a solution of 2,4-dichloropyrimidin-5-carboxynitrile (1A, 400 mg, 2.30 mmol) in t-BuOH (100 mL), 1-(methanesulfonyl)piperidin-4-amine (410 mg, 2.23 mmol) and DIEA (900 mg, 6.89 mmol) were added, and the reaction mixture was stirred at 85 °C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was ground in dichloromethane (20 mL). The precipitate was collected and dried to provide 4-chloro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-5-carboxynitrile (3A, 400 mg, 37%) as a white solid. LC-MS (ESI): m / z 316.1 [M+H] + .

[0536] t-BuOK (18 mg, 0.16 mmol) was added to a mixture of 4-chloro-2-[(1-methanesulfonylpiperidin-4-yl)amino]pyrimidine-5-carboxynitrile (3A, 40 mg, 0.06 mmol) and cis-1-methylcyclopentane-1,2-diol (intermediate I, 11 mg, 0.10 mmol) in DMSO (1 mL). The reaction mixture was stirred at 55 °C for 1.5 h. After completion, the resulting mixture was poured into ice water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluting with petroleum ether / ethyl acetate (from 1:0 to 1:2)) to give the racemic form of cis-4-((2-hydroxy-2-methylcyclopentyl)oxy)-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidine-5-carboxynitrile (3), which was further separated by chiral SFC to give:

[0537] Enantiomer 1 (3a, 100% ee); retention time: 3.16 min. LC-MS (ESI): m / z 396.2 [M+H] + ;

[0538] Enantiomer 2 (3b, 100% ee); retention time: 3.67 min. LC-MS (ESI): m / z 396.2 [M+H] +. 1 ¹H NMR (400MHz, DMSO-d6) (tautomer ratio approximately 1:1) δ 8.51 & 8.44 (s, 1H), 8.24 & 8.05 (d, J = 8.0Hz, 1H), 5.14–5.09 (m, 1H), 4.47 (d, J = 6.5Hz, 1H), 3.94–3.82 (m, 1H), 3.56–3.33 (m, 2H), 2.91–2.81 (m, 5H), 2.12–2.05 (m, 1H), 2.00–1.87 (m, 2H), 1.82–1.70 (m, 3H), 1.62–1.51 (m, 4H), 1.22 & 1.20 (s, 3H).

[0539] Analytical methods: Column: ChiralPak AD, 250×4.6mm ID, 5μm; Mobile phase: A, CO2, and B, MeOH (0.05% DEA); Gradient: 8min @ B 30%; Flow rate: 2.0mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0540] SFC Method: Instrument: MGⅡ preparative SFC (SFC-14); Column: ChiralPak AS, 250×30mm ID, 10μm; Mobile phase: A, CO2, and B, ethanol; Gradient: B 30%; Flow rate: 70mL / min; Back pressure: 100 bar; Wavelength: 220nm; Cycle time: approximately 4min; Column temperature: 38℃.

[0541] Figure 4. Cis-4-((2-hydroxy-2-methylcyclopentyl)oxy)-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidine

[0542] Synthesis of 5-formonitrile(4)

[0543]

[0544] A mixture of 4-chloro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidine-5-carboxynitrile (3A, 60 mg, 0.19 mmol), cis-4,4-difluoro-1-methylcyclopentane-1,2-diol (intermediate II, 35 mg, 0.23 mmol), and t-BuOK (43 mg, 0.38 mmol) in DMSO (1 mL) was stirred at 50 °C for 30 min. The resulting mixture was adjusted to pH 7 with formic acid and then separated by preparative HPLC to give cis-4-((4,4-difluoro-2-hydroxy-2-methylcyclopentyl)oxy)-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidine-5-carboxynitrile (4, 47 mg, 57%) in racemic form, which was further separated by chiral SFC to give:

[0545] Enantiomer 1 (4a, 96.3% ee); retention time: 1.22 min. LC-MS (ESI): m / z 432.2 [M+H] + . 1 ¹H NMR (400 MHz, DMSO-d6) (tautomer ratio approximately 1:1) δ 8.55 & 8.49 (s, 1H), 8.25 & 8.16 (d, J = 8.0 Hz, 1H), 5.36–5.22 (m, 1H), 5.13 & 5.12 (s, 1H), 3.99–3.80 (m, 1H), 3.56–3.53 (m, 2H), 2.88–2.82 (m, 6H), 2.44–2.20 (m, 3H), 1.98–1.81 (m, 2H), 1.62–1.52 (m, 2H), 1.31 & 1.30 (s, 3H).

[0546] Enantiomer 2 (4b, 95.5% ee); retention time: 1.45 min. LC-MS (ESI): m / z 432.2 [M+H] + .

[0547] Analytical methods: Column: Chiralpak AS-3, 150 x 4.6 mm ID, 3 μm; Mobile phase: 25% ethanol (0.05% DEA) in CO2; Flow rate: 2.5 mL / min; Column temperature: 35 °C.

[0548] SFC method: Instrument: MGⅡ preparative SFC (SFC-14); Column: ChiralPak AS, 250x 30mm ID, 10μm; Mobile phase: A, CO2, and B, isopropanol; Gradient: B 25%; Flow rate: 70mL / min; Back pressure: 100 bar; Column temperature: 38℃.

[0549] Figure 5. Cis-4-((2-hydroxy-2-methylcyclopentyl)oxy)-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidine

[0550] Synthesis of 5-formonitrile(5)

[0551]

[0552] A mixture of 4-chloro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidine-5-carboxynitrile (3A, 50 mg, 0.16 mmol), cis-1-methylcyclopentane-4,4-d2-1,2-diol (intermediate III, 21 mg, 0.17 mmol), and t-BuOK (36 mg, 0.32 mmol) in DMSO (1 mL) was stirred at 80 °C for 30 min. The reaction mixture was then adjusted to pH 7 with formic acid. The mixture was separated by preparative HPLC to provide cis-4-((2-hydroxy-2-methylcyclopentyl-4,4-d2)oxy)-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidine-5-carboxynitrile (5, 31 mg, 49%) in racemic form, which was further separated by chiral SFC to give:

[0553] Enantiomer 1 (5a, 100% ee); retention time: 3.22 min. LC-MS (ESI): m / z 398.2 [M+H] + . 1 ¹H NMR (400 MHz, DMSO-d6) (tautomer ratio approximately 1:1) δ 8.51 & 8.44 (s, 1H), 8.24 & 8.05 (d, J = 8.0 Hz, 1H), 5.14–5.17 (m, 1H), 4.48 & 4.47 (s, 1H), 3.94–3.82 (m, 1H), 3.55–3.51 (m, 2H), 2.89–2.81 (m, 5H), 2.08–1.98 (m, 1H), 1.95–1.83 (m, 2H), 1.80–1.64 (m, 2H), 1.60–1.52 (m, 3H), 1.21 & 1.19 (s, 3H).

[0554] Enantiomer 2 (5b, 100% ee); retention time: 3.74 min. LC-MS (ESI): m / z 398.2 [M+H] + .

[0555] Analytical methods: Column: ChiralPak IH, 100×4.6mm ID, 5μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 0.0min-1.0min@10%B, 1.0min-4.5min gradient (10%-40%B), 4.5min-7.0min@40%B, 7.0min-8.0min@10%B; Flow rate: 2.5mL / min; Column temperature: 40℃.

[0556] SFC method: Instrument: IMADZU PREP SOLUTION SFC; Column: ChiralPAK IH, 250×21.2mm I.D., 5μm; Mobile phase: A, CO2, and B, MEOH + 0.1% NH3·H2O; Gradient: B 40%; Flow rate: 40mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0557] Diagram 6.2 Synthesis of 2-((3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-4-((2-hydroxy-2-methylcyclopentyl)oxy)pyrimidine-5-carboxynitrile (6)

[0558]

[0559] Cs₂CO₃ (3.51 g, 10.8 mmol) was added to a mixture of 4-chloro-2-(methylthio)pyrimidin-5-carboxynitrile (6A, 1.00 g, 5.40 mmol) and cis-1-methylcyclopentane-1,2-diol (intermediate I, 0.75 g, 6.50 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature under N₂ for 1 hour. After completion, the reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography to provide cis-4-((2-hydroxy-2-methylcyclopentyl)oxy)-2-(methylthio)pyrimidin-5-carboxynitrile (6B, 1.30 g, 91%) as an oil. LC-MS(ESI): m / z 266.2 [M+H] + .

[0560] At 0 °C, m-CPBA (1.04 g, 6.00 mmol) was added to a solution of cis-4-((2-hydroxy-2-methylcyclopentyl)oxy)-2-(methylthio)pyrimidin-5-carboxynitrile (6B, 800 mg, 3.00 mmol) in dichloromethane (8 mL). The reaction mixture was stirred at room temperature under N2 for 2 h. Then, at 0 °C, the TFA salt of cis-3-fluoro-1-(methanesulfonyl)piperidine-4-amine (intermediate IX, 643 mg, 2.07 mmol) and triethylamine (1.27 g, 12.6 mmol) were added. The reaction mixture was stirred at room temperature under N2 for 15 min. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography and preparative HPLC to give cis-2-((3-fluoro-1-(methanesulfonyl)piperidin-4-yl)amino)-4-((2-hydroxy-2-methylcyclopentyl)oxy)pyrimidin-5-carboxynitrile (6) as a stereoisomeric mixture, which was further separated by chiral SFC to give:

[0561] Isomer 1 (6a, 100% ee); retention time: 3.45 min. LC-MS (ESI): m / z 414.2 [M+H] + ; 1 ¹H NMR (400MHz, CD₃OD) (tautomer ratio = 1:1) δ 8.40 & 8.36 (s, ¹H), 5.28–5.19 (m, ¹H), 5.00–4.80 (m, ¹H), 4.30–4.03 (m, 2H), 3.89–3.85 (m, ¹H), 3.30–3.00 (m, 2H), 2.93 & 2.91 (s, 3H), 2.25–2.15 (m, ¹H), 2.10–1.95 (m, ¹H), 1.95–1.80 (m, 4H), 1.75–1.60 (m, 2H), 1.30 (s, 3H).

[0562] Isomer 2 (6b, 99.6% ee); retention time: 3.58 min. LC-MS (ESI): m / z 414.2 [M+H] + .

[0563] Isomer 3 (6c, 96.2% ee); retention time: 4.23 min. LC-MS (ESI): m / z 414.2 [M+H] + .

[0564] Isomer 4 (6d, 100% ee); retention time: 4.41 min. LC-MS (ESI): m / z 414.2 [M+H] + .

[0565] Analytical methods: Column: Chiralpak AS-3, 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Gradient: from 5% to 40% B over 5 min, held at 40% for 2.5 min, then held at 5% B for 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35℃.

[0566] SFC method: Instrument: Waters Thar 80 preparative SFC; Column: Chiralpak AS, 250×21.2mm I.D., 5μm; Mobile phase: A, CO2, and B, MeOH + 0.1% NH3·H2O; Gradient: B 40%; Flow rate: 40mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0567] Diagram illustrating the synthesis of 7,4-((4,4-difluoro-2-hydroxy-2-methylcyclohexyl)oxy)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carboxynitrile (7)

[0568]

[0569] Diisopropylethylamine (3 mL, 16.0 mmol) was added to a mixture of 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-amine hydrochloride (intermediate X, 1.30 g, 4.63 mmol) and 2,4-dichloropyrimidin-5-carboxynitrile (3A, 1.20 g, 6.90 mmol) in t-BuOH (10 mL). The reaction mixture was stirred at 50 °C under N2 for 0.5 h. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography and preparative HPLC to provide 4-chloro-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carboxynitrile (7A, 800 mg, 45%) as a white solid. LC-MS (ESI): m / z 382.1 [M+H] + .

[0570] t-BuOK (176 mg, 1.57 mmol) was added to a mixture of 4-chloro-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidin-5-carboxynitrile (7A, 200 mg, 0.52 mmol) and cis-5,5-difluoro-1-methylcyclohexane-1,2-diol (intermediate VI, 131 mg, 0.79 mmol) in DMSO (2 mL). The reaction mixture was stirred at 50 °C under N2 for 2 hours. After completion, the mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography and preparative HPLC to give the racemic form of cis-4-((4,4-difluoro-2-hydroxy-2-methylcyclohexyl)oxy)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carboxynitrile (7), which was further separated by chiral SFC to give:

[0571] Enantiomer 1 (7a, 100% ee); retention time: 2.73 min. LC-MS (ESI): m / z 512.2 [M+H] + ; 1 ¹H NMR (400 MHz, DMSO-d6) (tautomer ratio approximately 1:1) δ 8.50 & 8.46 (s, 1H), 8.34 & 8.32 (s, 1H), 8.27 & 8.12 (d, J = 8.0 Hz, 1H), 7.78 & 7.77 (s, 1H), 5.20–5.12 (m, 1H), 4.92 & 4.82 (s, 1H), 3.90 (s, 3H), 3.79–3.78 (m, 1H), 3.55–3.48 (m, 2H), 2.51–2.49 (m, 2H), 2.40–1.89 (m, 8H), 1.64–1.58 (m, 2H), 1.20 & 1.18 (s, 3H).

[0572] Enantiomer 2 (7b, 100% ee); retention time: 4.71 min. LC-MS (ESI): m / z 512.2 [M+H] + .

[0573] Analytical methods: Column: ChiralPak IH, 100×4.6mm ID, 5μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 8min@20%B; Flow rate: 2.5mL / min; Column temperature: 40℃.

[0574] SFC Method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralPak IH, 250×21.2mm I.D., 5μm; Mobile Phase: A, CO2, and B, MeOH + 0.1% NH3·H2O; Gradient: B 30%; Flow Rate: 40mL / min; Back Pressure: 100 bar; Column Temperature: 35℃; Wavelength: 254nm; Cycle Time: 8min; Elution Time: 2.3hr.

[0575] Diagram 8.2-((1-((1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-4-((1-methylcyclopentyl)methoxy)pyrimidine

[0576] Synthesis of 5-formonitrile(8)

[0577]

[0578] At 0 °C, a solution of 2,4-dichloropyrimidin-5-carboxylate (1A, 435 mg, 2.50 mmol) in DMF (1 mL) was added dropwise to a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (500 mg, 2.50 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.50 mmol) in DMF (2 mL). The mixture was then stirred at room temperature for 1 hour. After completion, the mixture was separated by preparative HPLC to give tert-butyl 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate (8A, 420 mg, 50%). LC-MS (ESI): m / z 338.1 [M+H] + .

[0579] t-BuOK (125 mg, 1.12 mmol) was added to a mixture of tert-butyl 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate (8A, 216 mg, 0.56 mmol) and (1-methylcyclopentyl)methanol (96 mg, 0.84 mmol) in anhydrous DMSO (2 mL). The mixture was stirred at 80 °C for 30 min. The mixture was then cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (50 mL x 2). The organic layer was collected, washed with brine, dried over Na2SO4, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give tert-butyl 4-((5-cyano-4-((1-methylcyclopentyl)methoxy)pyrimidin-2-yl)amino)piperidine-1-carboxylate (8B, 200 mg, 86%). LC-MS (ESI): m / z 416.3 [M+H] + .

[0580] HCl (4M in dioxane, 1 mL) was added to a solution of tert-butyl 4-((5-cyano-4-((1-methylcyclopentyl)methoxy)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (8B, 200 mg, 0.48 mmol) in methanol (3 mL). The reaction mixture was stirred at 40 °C for 1 h and then concentrated under reduced pressure to give 4-((1-methylcyclopentyl)methoxy)-2-(piperidine-4-ylamino)pyrimidin-5-carboxylonitrile (8C, 155 mg, 92%) as the HCl salt. LC-MS (ESI): m / z 316.2 [M+H] + .

[0581] At 0 °C, a solution of 1-benzyl-1H-pyrazole-4-sulfonyl chloride (73 mg, 0.28 mmol) in dry dichloromethane (2 mL) was carefully added to a mixture of 4-((1-methylcyclopentyl)methoxy)-2-(piperidin-4-ylamino)pyrimidin-5-carboxylonitrile (8C, 100 mg, 0.28 mmol) and N,N-diisopropylethylamine (140 μL, 0.85 mmol) in anhydrous dichloromethane (2 mL). The mixture was stirred at room temperature for 1 hour. After completion, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give 2-((1-((1-benzyl-1H-pyrazole-4-yl)sulfonyl)piperidin-4-yl)amino)-4-((1-methylcyclopentyl)methoxy)pyrimidin-5-carboxylonitrile (8D, 100 mg, 66%) as a white solid. LC-MS(ESI): m / z 536.2 [M+H] + .

[0582] t-BuOK (57 mg, 0.51 mmol) was added to a solution of 2-((1-((1-benzyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-4-((1-methylcyclopentyl)methoxy)pyrimidin-5-carboxylonitrile (8D, 90 mg, 0.17 mmol) in DMSO (1 mL), and the mixture was stirred overnight at room temperature. After completion, the mixture was filtered, and the filtrate was separated by preparative HPLC to give 2-((1-((1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-4-((1-methylcyclopentyl)methoxy)pyrimidin-5-carboxylonitrile (8, 24.2 mg, 29%) as a white solid. LC-MS (ESI): m / z 446.2 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ8.49&8.45(s,1H),8.30&8.16(d,J=7.6Hz,1H),8.09(s,2H),4.14(d,J=14.4Hz,2H),3.87-3.64( m,1H),3.51-3.43(m,2H),2.48-2.34(m,2H),1.96-1.87(m,2H),1.67-1.43(m,8H),1.38-1.30(m,2H),1.05&1.03(s,3H).

[0583] Diagram illustrating the synthesis of 9,4-((5-cyano-4-(piperidin-1-yl)pyrimidin-2-yl)amino)benzenesulfonamide (65)

[0584]

[0585] A solution of 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)benzenesulfonamide (1B, 50 mg, 0.16 mmol), piperidine (20 μL, 0.21 mmol), and N,N-diisopropylethylamine (33 mg, 0.26 mmol) in dioxane (2 mL) was stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (3 mL), and a precipitate formed. The mixture was filtered, and the filter cake was ground in methanol (5 mL). The solid was recovered and dried to give 4-((5-cyano-4-(piperidin-1-yl)pyrimidin-2-yl)amino)benzenesulfonamide (65, 20 mg, 35%). LC-MS (ESI): m / z 359.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.04(br s,1H),8.34(s,1H),7.72(d,J=8.8Hz,2H),7.64(d,J=8.8Hz,2H),7.10(s,2H),3.76-3.74(m,4H),1.56-1.51(m,6H).

[0586] Diagram illustrating the synthesis of 10,4-((5-cyano-4-(piperidin-1-yl)pyrimidin-2-yl)amino)-N-(oxetane-3-yl)benzenesulfonamide (66)

[0587]

[0588] To a solution of 2,4-dichloro-5-iodopyrimidine (66A, 10.0 g, 36.4 mmol) in dioxane (90 mL), piperidine (3.41 g, 40.0 mmol) and diisopropylethylamine (14.1 g, 109 mmol) were added. The reaction mixture was stirred at 25 °C for 15 hours. After completion, the mixture was diluted with H₂O (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to provide 2-chloro-5-iodo-4-(piperidin-1-yl)pyrimidine (66B, 10.0 g, 85%) as a white solid. LC-MS (ESI): m / z 324.1 [M+H] + .

[0589] A mixture of 2-chloro-5-iodo-4-(piperidin-1-yl)pyrimidine (66B, 3.00 g, 9.27 mmol), Zn(CN)₂ (2.18 g, 18.5 mmol), Zn (606 mg, 9.27 mmol), Pd(PPh₃)₄ (1.07 g, 0.93 mmol) and 1,1'-bis(diphenylphosphine)ferrocene (dppf) (1.03 g, 1.85 mmol) in dioxane (15 mL) was purged with N₂ and then subjected to microwave conditions with stirring at 60 °C for 1.5 hours. Afterward, the mixture was passed through a small piece of... The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was separated by rapid chromatography to provide 2-chloro-4-(piperidin-1-yl)pyrimidin-5-carboxynitrile (66C, 0.9 g, 43%) as a white solid. LC-MS (ESI): m / z 223.1 [M+H] + .

[0590] Pd(OAc)₂ (5 mg, 0.01 mmol) was added to a mixture of 2-chloro-4-(piperidin-1-yl)pyrimidin-5-carboxynitrile (66C, 30 mg, 0.13 mmol), 4-amino-N-(oxetane-3-yl)benzenesulfonamide (intermediate XI, 46 mg, 0.20 mmol), Cs₂CO₃ (132 mg, 0.41 mmol), and XantPhos (16 mg, 0.03 mmol) in dioxane (3 mL), and the reaction mixture was stirred overnight at 100 °C under N₂ atmosphere. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 4-((5-cyano-4-(piperidin-1-yl)pyrimidin-2-yl)amino)-N-(oxetane-3-yl)benzenesulfonamide (66, 12 mg, 22%). LC-MS(ESI): m / z 415.1 [M+H] +. 1 H NMR(400MHz,DMSO-d6)δ10.23(br s,1H),8.48(s,1H),8.37(br s,1H),7.88(d,J=8.8Hz,2H),7.71(d,J=8.8Hz,2H),4.49(t,J=6.8Hz,2H),4. 40-4.31(m,1H),4.24(t,J=6.4Hz,2H),3.90-3.86(m,4H),1.68-1.64(m,6H).

[0591] Diagram illustrating the synthesis of 11,4-((5-cyano-4-(4-hydroxyphenyl)pyrimidin-2-yl)amino)benzenesulfonamide (92)

[0592]

[0593] A solution of K₂CO₃ (116 mg, 0.83 mmol) in H₂O (1 mL) was added to a mixture of 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)benzenesulfonamide (1B, 50 mg, 0.16 mmol) and (4-hydroxyphenyl)boronic acid (27 mg, 0.19 mmol) in dioxane (4 mL). The reaction mixture was degassed and backfilled three times with N₂. Pd(t-Bu₃P)₂ (8 mg, 0.02 mmol) was added and the resulting mixture was stirred at 90 °C for 3 h under N₂ atmosphere. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated by preparative HPLC to give 4-((5-cyano-4-(4-hydroxyphenyl)pyrimidin-2-yl)amino)benzenesulfonamide (92, 11 mg, 19%). LC-MS (ESI): m / z 368.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.73(br s,1H),8.94(s,1H),7.96(d,J=8.8Hz,2H),7.95(d,J=8.8Hz,2H),7.79(d,J=8.8Hz,2H),7.25(s,2H),6.98(d,J=8.8Hz,2H).

[0594] Figure 12. Synthesis of cis-4-((4-((2-hydroxycyclopentyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (99)

[0595]

[0596] To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (99A, 2.00 g, 9.22 mmol) in t-BuOH (50 mL), 4-aminobenzene-1-sulfonamide (1.59 g, 9.22 mmol) and N,N-diisopropylethylamine (4.5 mL, 27.7 mmol) were added. The reaction mixture was stirred at 30 °C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was milled in dichloromethane (30 mL). The product was recovered and dried to provide 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (99B, 0.70 g, 22%) as a white solid. LC-MS (ESI): m / z 353.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.0(s,1H),8.89(s,1H),7.88(d,J=8.0Hz,2H),7.80(d,J=8.0Hz,2H),7.28(s,2H).

[0597] Cis-cyclopentane-1,2-diol (64 mg, 0.62 mmol) was added to a mixture of 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (99B, 200 mg, 0.57 mmol) and t-BuOK (127 mg, 1.13 mmol) in DMSO (3 mL). The reaction mixture was stirred at 90 °C for 20 min. After stirring, the reaction mixture was poured into ice-cold saturated NH4Cl solution (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give cis-4-((4-((2-hydroxycyclopentyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (99) in racemic form, which was further separated by chiral SFC to give:

[0598] Enantiomer 1 (99a, 92.9% ee); retention time: 3.19 min. LC-MS (ESI): m / z 419.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.56(s,1H),7.90(d,J=8.0Hz,2H),7.77(d,J=8.0Hz,2H),7.22(s,2H),5.4 0-5.32(m,1H),4.71(d,J=4.0Hz,1H),4.28-4.22(m,1H),2.10-1.92(m,1H),1.92-1.67(m,3H),1.74-1.45(m,2H).

[0599] Enantiomer 2 (99b, 91.1% ee); retention time: 4.21 min. LC-MS (ESI): m / z 419.1 [M+H] + .

[0600] Analytical methods: Column: ChiralPak AD, 250×4.6mm ID, 5μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 10min@40%; Flow rate: 2.0mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0601] SFC method: Instrument: Waters UPC2 analytical SFC; Column: ChiralPAK AD, 250×21.2mm ID, 5μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 10min@40%; Flow rate: 40mL / min; Column temperature: 35℃.

[0602] Figure 13. Synthesis of cis-4-((4-((3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (100)

[0603]

[0604] Sodium carbonate (1M aqueous solution, 45 mL, 45 mmol) was added to a mixture of methyl-d3-amine monohydrochloride (100A, 1.00 g, 14.8 mmol) and 4-nitrobenzenesulfonyl chloride (4.00 g, 17.8 mmol) in dichloromethane (100 mL). The mixture was stirred at room temperature for 2 hours. After stirring, the mixture was extracted with dichloromethane (200 mL x 2). The extracts were combined, dried over Na2SO4, and concentrated under reduced pressure to give N-(methyl-d3)-4-nitrobenzenesulfonamide (100B, 2.97 g, 91%).

[0605] Palladium (10% carbon-supported palladium, 300 mg) was added to a solution of N-(methyl-d3)-4-nitrobenzenesulfonamide (100B, 2.97 g, 13.6 mmol) in methanol (30 mL). The mixture was stirred at room temperature for 5 hours under H2 at one atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4-amino-N-(methyl-d3)benzenesulfonamide (100C, 2.40 g, 94%) as a white solid. LC-MS (ESI): m / z 190.1 [M+H] + .

[0606] N,N-diisopropylethylamine (4.92 g, 38.1 mmol) was added to a mixture of 4-amino-N-(methyl-d3)benzenesulfonamide (100°C, 2.40 g, 12.7 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (99A, 3.30 g, 15.2 mmol) in t-BuOH (60 mL). The reaction mixture was stirred overnight at 80°C under N2. After completion, the mixture was concentrated under reduced pressure to produce a residue. The residue was diluted with H2O (60 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure (until 2–3 mL of the mixture remained). The mixture was filtered and the filter cake was ground in dichloromethane (10 mL) to form a yellow solid. The yellow solid was collected and dried to provide 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (100D, 2.12 g, 45%). LC-MS (ESI): m / z 370.1 [M+H] + .

[0607] To a solution of 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (100D, 150 mg, 0.41 mmol) in DMSO (2 mL), cis-tetrahydro-2H-pyran-3,4-diol (intermediate V, 96 mg, 0.81 mmol) and t-BuOK (137 mg, 1.20 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours. After completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to produce a residue. The residue was separated by silica gel column chromatography to give the racemic form of cis-4-((4-((3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (100), which was further separated by chiral SFC to give:

[0608] Enantiomer 1 (100a, 99% ee); retention time: 4.20 min. LC-MS (ESI): m / z 452.2 [M+H] + ;1H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.60(s,1H),7.92(d,J=8.8Hz,2H),7.73(d,J=8.7Hz,2H),7.27(s ,1H),5.62–5.56(m,1H),5.05(d,J=4.9Hz,1H),3.94–3.85(m,1H),3.69-3.49(m,4H),2.10-1.81(m,2H).

[0609] Enantiomer 2 (100b, 98.6% ee); retention time: 5.41 min. LC-MS (ESI): m / z 452.2 [M+H] + ;

[0610] Analytical methods: Column: ChiralCel OD, 250×4.6mm ID, 5μm; Mobile phase: A, CO2, and B, MeOH (0.05% DEA); Gradient: 8min @ B 30%; Flow rate: 2.0mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0611] SFC Method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralCel OD, 250×21.2mm I.D., 5μm; Mobile Phase: A, CO2, and B, MeOH + 0.1% NH3·H2O; Gradient: B 25%; Flow Rate: 50mL / min; Back Pressure: 100 bar; Column Temperature: 35℃; Wavelength: 256nm; Cycle Time: 8min; Elution Time: 1.5hr.

[0612] Figure 14. Synthesis of cis-3-fluoro-4-((4-((3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (101)

[0613]

[0614] At 80 °C, a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (99A, 98 μL, 0.72 mmol) in t-BuOH (0.1 mL) was added dropwise to a mixture of 4-amino-3-fluoro-N-(methyl-d3)benzenesulfonamide (intermediate XII, 100 mg, 0.48 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.97 mmol) in t-BuOH (1 mL). The mixture was stirred at 80 °C for 2 hours. Then, a second batch of a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (99A, 98 μL, 0.72 mmol) in t-BuOH (0.1 mL) was added dropwise at 80 °C. The mixture was stirred at 80 °C for another 12 hours. After completion, the mixture was separated by preparative HPLC to give 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoro-N-(methyl-d3)benzenesulfonamide (101A, 45 mg, 24%) as a yellow solid. 1 H NMR (500MHz, DMSO-d6) δ10.71 (s, 1H), 8.84 (s, 1H), 7.93 (t, J = 7.9Hz, 1H), 7.72-7.62 (m, 2H), 7.53 (s, 1H).

[0615] t-BuOK (70 mg, 0.62 mmol) was added to a mixture of 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoro-N-(methyl-d3)benzenesulfonamide (101A, 80 mg, 0.21 mmol) and cis-tetrahydro-2H-pyran-3,4-diol (intermediate V, 49 mg, 0.42 mmol) in dimethyl sulfoxide (1 mL). The mixture was stirred at 90 °C for 1 hour. The reaction mixture was adjusted to pH 7 with formic acid and then separated by preparative HPLC to give cis-3-fluoro-4-((4-((3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (101, 27 mg, 28%) in racemic form, which was further separated by chiral SFC to give:

[0616] Enantiomer 1 (101a, 100% ee); retention time: 4.73 min. LC-MS (ESI): m / z 470.1 [M+H] + ; 1¹H NMR (400MHz, DMSO-d6) (tautomer ratio = 1:1) δ 10.05 (s, 1H), 8.55 (s, 1H), 8.03 (t, J = 8.4Hz, 1H), 7.82–7.62 (m, 2H), 7.50 (s, 1H), 5.45–5.41 (m, 1H), 5.02 (d, J = 4.9Hz, 1H), 3.84–3.81 (m, 1H), 3.61–3.54 (m, 4H), 2.01–1.78 (m, 2H).

[0617] Enantiomer 2 (101b, 100% ee); retention time: 5.39 min. LC-MS (ESI): m / z 470.1 [M+H] + .

[0618] Analytical methods: Column: ChiralPak C-IG, 100×4.6mm ID, 5μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 0.0min-1.0min@10%B, 1.0min-4.5min gradient (10%-40%B), 4.5min-7.0min@40%B, 7.0min-8.0min@10%B; Flow rate: 2.5mL / min; Column temperature: 40℃.

[0619] SFC method: Instrument: IMADZU PREP SOLUTION SFC; Column: ChiralPak C-IG, 250×21.2mm I.D., 5μm; Mobile phase: A, CO2, and B, MEOH + 0.1% NH3·H2O; Gradient: B 40%; Flow rate: 40mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0620] Diagram 15.4-((4-((5-hydroxyoxetane-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl)

[0621] Synthesis of -d3)benzenesulfonamide (102)

[0622]

[0623] At 0 °C, t-BuOK (14 mg, 0.12 mmol) was added to a mixture of oxepane-4,5-diol (intermediate VII, 16 mg, 0.12 mmol) and 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (100D, 15 mg, 0.04 mmol) in DMSO (1 mL). The reaction mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, the solution was poured into a saturated solution of NH4Cl (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give 4-((4-((5-hydroxyoxetane-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (102), which was further separated by chiral SFC to give:

[0624] Diastereomer 1 (102a, 96.7% ee); retention time: 1.37 min. LC-MS (ESI): m / z 466.3 [M+H] + ;

[0625] Diastereomer 2 (102b, 100% ee); retention time: 1.45 min. LC-MS (ESI): m / z 466.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.51(br s,1H),8.60(s,1H),7.95(d,J=8.0Hz,2H),7.74(d,J=8.0Hz,2H),7.29(s,1H),5.43-5.39(m,1H),5.06(d,J =4.0Hz,1H),4.02-3.93(m,1H),3.75-3.60(m,4H),2.21-2.15(m,1H),2.00-1.94(m,2H),1.81-1.74(m,1H).

[0626] Diastereomer 3 (10²c, 95.3% ee); retention time: 1.69 min. LC-MS (ESI): m / z 466.2 [M+H] + .

[0627] Diastereomer 4 (10² d, 100% ee); retention time: 1.89 min. LC-MS (ESI): m / z 466.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.51(br,s,1H),8.60(s,1H),7.95(d,J=8.0Hz,2H),7.74(d,J=8.0Hz,2H),7.29(s,1H),5.42-5.39( m,1H),5.06(d,J=4.0Hz,1H),3.97-3.93(m,1H),3.75-3.61(m,4H),2.24-2.15(m,1H),2.00-1.94(m,2H),1.81-1.76(m,1H).

[0628] Analytical methods: Instrument: Waters UPC2 analytical SFC (SFC-H); Column: ChiralPak AD, 150×4.6mm I.D., 3μm; Mobile phase: A, CO2, and B, ethanol (0.05% DEA); Gradient: B 40%; Flow rate: 2.5mL / min; Back pressure: 100 bar; Column temperature: 35℃; Wavelength: 220nm.

[0629] SFC method:

[0630] Round 1: Instrument: MGⅡ preparative SFC (SFC-14); Column: ChiralPak AD, 250x30mm ID, 10μm; Mobile phase: A, CO2, and B, isopropanol (0.1% NH3·H2O); Gradient: B 35%. Flow rate: 80mL / min; Back pressure: 100 bar; Column temperature: 38℃.

[0631] Second round: Instrument: MGⅡ preparative SFC (SFC-14); Column: ChiralPak AD, 250x30mm ID, 10μm; Mobile phase: A, CO2, and B, ethanol (0.1% NH3·H2O); Gradient: B 35%; Flow rate: 80mL / min; Back pressure: 100 bar; Column temperature: 38℃.

[0632] Figure 16. Synthesis of cis-4-((4-((3-hydroxyoxetane-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (103)

[0633]

[0634] t-BuOK (91 mg, 0.81 mmol) was added to a mixture of 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (100D, 100 mg, 0.27 mmol) and cis-oxetane-3,4-diol (intermediate VIII, 42 mg, 0.33 mmol) in DMSO (1 mL). The mixture was stirred at 80 °C for 2 hours. The mixture was adjusted to pH 7 with formic acid and then separated by preparative HPLC to provide cis-4-((4-((3-hydroxyoxetane-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (103, 27 mg, 28%) in racemic form, which was further separated by chiral SFC to give:

[0635] Enantiomer 1 (10³a, 100% ee); retention time: 4.67 min. LC-MS (ESI): m / z 466.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.60(s,1H),7.94(d,J=8.8Hz,2H),7.73(d,J=8.8Hz,2H),7.30(s,1H),5 .29(s,1H),5.16(d,J=5.6Hz,1H),3.81-3.72(m,3H),3.65-3.62(m,2H),2.11-1.94(m,2H),1.88-1.78(m,2H).

[0636] Enantiomer 2 (10³b, 95.1% ee); retention time: 5.08 min. LC-MS (ESI): m / z 466.2 [M+H] + .

[0637] Analytical methods: Column: ChiralPak C-IG, 100×4.6mm ID, 5μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 0.0min-1.0min@10%B, 1.0min-4.5min gradient (10%-40%B), 4.5min-7.0min@40%B, 7.0min-8.0min@10%B; Flow rate: 2.5mL / min; Column temperature: 40℃.

[0638] SFC method: Instrument: IMADZU PREP SOLUTION SFC; Column: ChiralPak C-IG, 250×21.2mm I.D., 5μm; Mobile phase: A, CO2, and B, MeOH + 0.1% NH3·H2O; Gradient: B 40%; Flow rate: 40mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0639] Figure 17. Synthesis of cis-3-methyl-4-((2-((1-(methanesulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)tetrahydrofuran-3-ol (104)

[0640]

[0641] N,N-diisopropylethylamine (1.48 mL, 9.00 mmol) was added to a mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (99A, 651 mg, 3.00 mmol) and 1-(methanesulfonyl)piperidin-4-amine (534 mg, 3.00 mmol) in t-BuOH (10 mL). The mixture was stirred at 80 °C for 3 hours. After completion, the mixture was concentrated under reduced pressure, and the residue was subjected to preparative HPLC to give 4-chloro-N-(1-(methanesulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidine-2-amine (104A, 367 mg, 30%). LC-MS (ESI): m / z 359.0 [M+H] + .

[0642] t-BuOK (83 mg, 0.74 mmol) was added to a mixture of 4-chloro-N-(1-(methanesulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (104A, 88 mg, 0.25 mmol) and cis-3-methyltetrahydrofuran-3,4-diol (intermediate IV, 59 mg, 0.50 mmol) in DMSO (3 mL). The reaction mixture was stirred at 90 °C for 30 min. After completion, the mixture was cooled to room temperature and then subjected to preparative HPLC to provide cis-3-methyl-4-((2-((1-(methanesulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)tetrahydrofuran-3-ol (104, 34 mg, 28%) in racemic form, which was further separated by chiral SFC to give:

[0643] Enantiomer 1 (10⁴a, 99.6% ee); retention time: 1.14 min. LC-MS (ESI): m / z 441.2 [M+H] + ; 1¹H NMR (400MHz, DMSO-d6) (tautomer ratio approximately 1:1) δ 8.35 & 8.31 (s, 1H), 7.99 & 7.78 (d, J = 8.0 Hz, 1H), 5.32–5.22 (m, 1H), 4.83 & 4.81 (s, 1H), 4.22–4.16 (m, 1H), 3.91–3.88 (m, 1H), 3.77–3.75 (m, 1H), 3.57–3.53 (m, 4H), 2.90–2.84 (m, 5H), 2.04–1.91 (m, 2H), 1.57–1.51 (m, 2H), 1.33 & 1.23 (s, 3H).

[0644] Enantiomer 2 (104b, 98.7% ee); retention time: 1.43 min. LC-MS (ESI): m / z 441.2 [M+H] + .

[0645] Analytical methods: Column: Chiralpak AD-3, 150 x 4.6 mm ID, 3 μm; Mobile phase: 30% ethanol (0.05% DEA) in CO2; Flow rate: 2.5 mL / min; Column temperature: 35 °C.

[0646] SFC method: Instrument: MGⅡ preparative SFC (SFC-14); Column: ChiralPak AD, 250x 30mm ID, 10μm; Mobile phase: A, CO2, and B, ethanol (0.1% NH3·H2O); Gradient: B 25%; Flow rate: 70mL / min; Back pressure: 100 bar; Column temperature: 38℃.

[0647] Diagram illustrating the synthesis of 18,4-((5-chloro-4-((2-hydroxycyclopentyl)oxy)pyrimidin-2-yl)amino)-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (130)

[0648]

[0649] At 0 °C, t-BuOK (0.43 g, 3.86 mmol) was added to a mixture of 2,4,5-trichloropyrimidine (130A, 0.68 g, 3.68 mmol) and cis-cyclopentan-1,2-diol (0.39 g, 3.86 mmol) in DMSO (10 mL), and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was then poured into a cold saturated solution of NH4Cl (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give cis-2-((2,5-dichloropyrimidine-4-yl)oxy)cyclopentan-1-ol (130B, 0.38 g, 41%) as a white solid. LC-MS (ESI): m / z 249.0 [M+H] + .

[0650] Hydrogen chloride (4M in dioxane, 0.12 mL, 0.47 mmol) was added to a mixture of 2-[(2,5-dichloropyrimidin-4-yl)oxy]cyclopentan-1-ol (130B, 58 mg, 0.23 mmol) and 4-amino-N-(oxan-4-yl)benzene-1-sulfonamide (63 mg, 0.24 mmol) in anhydrous t-BuOH (1 mL). The reaction mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, it was poured into a saturated aqueous solution of NH4Cl (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the racemic form of cis-4-((5-chloro-4-((2-hydroxycyclopentyl)oxy)pyrimidin-2-yl)amino)N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (130), which was further separated by chiral SFC to give:

[0651] Enantiomer 1 (130a, 98.3% ee); retention time: 4.07 min. LC-MS (ESI): m / z 469.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.06(br s,1H),8.35(s,1H),7.88(d,J=9.0Hz,2H),7.72(d,J=8.9Hz,2H),7.59(d,J=7.0Hz,1H),5.27-5.21(m,1H),4.72(d,J=4.8Hz,1H),4.29-4.19 (m,1H),3.74-3.66(m,2H),3.33-3.20(m,3H),1.89-1.82(m,1H),1.87 -1.78(m,3H),1.71-1.61(m,1H),1.59-1.49(m,3H),1.40-1.28(m,2H).

[0652] Enantiomer 2 (130b, 98.7% ee); retention time: 5.95 min. LC-MS (ESI): m / z 469.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.07(br s,1H),8.35(s,1H),7.88(d,J=8.9Hz,2H),7.72(d,J=8.9Hz,2H),7.59(d,J=7.2Hz,1H),5.28-5.23(m,1H),4.72(d,J=4.8Hz,1H),4.30-4.20 (m,1H),3.75-3.67(m,2H),3.24-3.19(m,3H),2.07-2.01(m,1H),1.88 -1.78(m,3H),1.70-1.60(m,1H),1.55-1.45(m,3H),1.37-1.29(m,2H).

[0653] Analytical methods: Column: ChiralCel OD, 250 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, MeOH (0.05% DEA); Gradient: 8 min @ B 40%; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 35 °C.

[0654] SFC method: Instrument: Waters UPC2 analytical SFC; Column: ChiralPak AD, 250×4.6mm ID, 5μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 10min@40%; Flow rate: 2.0mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0655] Figure 19. Cis-4-((5-bromo-4-((2-hydroxycyclopentyl)oxy)pyrimidin-2-yl)amino)N-(3-methyloxetane)

[0656] Synthesis of 3-yl)benzenesulfonamide (131)

[0657]

[0658] t-BuOK (67 mg, 0.60 mmol) was added to a mixture of 5-bromo-2,4-dichloropyrimidine (131A, 113 mg, 0.50 mmol) and cis-cyclopentan-1,2-diol (50 mg, 0.50 mmol) in DMSO (2 mL), and the mixture was stirred at room temperature for 2 hours. After completion, the mixture was separated by preparative HPLC to provide cis-2-((5-bromo-2-chloropyrimidin-4-yl)oxy)cyclopentan-1-ol (131B, 108 mg, 74%) as a white solid. LC-MS (ESI): m / z 293.0 [M+H] + .

[0659] Under a nitrogen atmosphere, Pd(OAc)₂ (4 mg, 0.02 mmol), Xantphos (18 mg, 0.03 mmol), and Cs₂CO₃ (204 mg, 0.63 mmol) were added to a mixture of cis-2-[(5-bromo-2-chloropyrimidin-4-yl)oxy]cyclopentan-1-ol (131B, 92 mg, 0.31 mmol) and 4-amino-N-(3-methyloxetane-3-yl)benzene-1-sulfonamide (intermediate XIV, 76 mg, 0.31 mmol) in anhydrous dioxane (1 mL). The reaction mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL), filtered through a diatomaceous earth mat, and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the racemic form of cis-4-({5-bromo-4-[(2-hydroxycyclopentyl)oxy]pyrimidin-2-yl}amino)-N-(3-methyloxetane-3-yl)benzene-1-sulfonamide (131), which was further separated by chiral SFC to give:

[0660] Enantiomer 1 (131a, 94.2% ee); retention time: 4.39 min. LC-MS (ESI): m / z 499.1 & 501.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.10(br s,1H),8.43(s,1H),8.14(br s,1H),7.90(d,J=8.8Hz,2H),7.72(d,J=8.8Hz,2H),5.33-5.19(m,1H),4.71(d,J=4.8Hz,1H),4.53(d,J=5.6Hz,2H ),4.32-4.22(m,1H),4.08(d,J=6.0Hz,2H),2.11-1.97(m,1H),1.91-1.77(m,3H),1.67-1.55(m,2H),1.43(s,3H).

[0661] Enantiomer 2 (131b, 93.9% ee); retention time: 7.54 min. LC-MS (ESI): m / z 499.1 & 501.1 [M+H] + .

[0662] Analytical methods: Column: ChiralCel OD, 250×21.2mm ID, 5μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 10min@40%; Flow rate: 40mL / min; Column temperature: 35℃.

[0663] SFC Method: Instrument: Waters UPC2 analytical SFC; Column: ChiralPak AD, 250 x 4.6 mm I.D., 5 μm; Mobile phase: A, CO2, and B, methanol (0.05% DEA); Gradient: 10 min @ 40%; Flow rate: 2.0 mL / min; Back pressure: 100 bar; Column temperature: 35 °C.

[0664] Figure 20. Synthesis of cis-4-((4-((2-hydroxycyclopentyl)oxy)-5-methylpyrimidin-2-yl)amino)benzenesulfonamide (132)

[0665]

[0666] At 0 °C, NaH (60% in mineral oil, 78 mg, 1.96 mmol) was added to a solution of cis-cyclopentan-1,2-diol (100 mg, 0.98 mmol) in THF (3 mL), and the reaction mixture was heated to 40 °C. Then, a solution of 2,4-dichloro-5-methylpyrimidine (132A, 144 mg, 0.88 mmol) in THF (3 mL) was added dropwise. After completion, the reaction mixture was poured into an ice-cold saturated NH4Cl solution (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was then separated by silica gel column chromatography to give cis-2-((2-chloro-5-methylpyrimidin-4-yl)oxy)cyclopentan-1-ol (132B, 150 mg, 75%) as a white solid. LC-MS(ESI): m / z 229.0 [M+H] + .

[0667] A mixture of cis-2-((2-chloro-5-methylpyrimidin-4-yl)oxy]cyclopentan-1-ol (132B, 100 mg, 0.44 mmol), 4-aminobenzene-1-sulfonamide (114 mg, 0.66 mmol), Cs₂CO₃ (427 mg, 1.31 mmol), Pd(OAc)₂ (10 mg, 0.04 mmol), and XantPhos (51 mg, 0.09 mmol) in dioxane (3 mL) was degassed and backfilled three times with N₂, then sealed in a tube and stirred in a microwave at 100 °C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to provide cis-4-((4-(((2-hydroxycyclopentyl)oxy)-5-methylpyrimidin-2-yl)amino)benzene-1-sulfonamide (132) in racemic form, which was further separated by chiral SFC to give:

[0668] Enantiomer 1 (132a, 96.1% ee); retention time: 3.20 min. LC-MS (ESI): m / z 365.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.69(s,1H),8.08(s,1H),7.88(d,J=8.9Hz,2H),7.69(d,J=8.8Hz,2H),7.13(s,2H ),5.27-5.19(m,1H),4.62(d,J=5.0Hz,1H),4.26-4.17(m,1H),2.06-1.97(m,4H),1.88-1.75(m,3H),1.72 -1.62(m,1H),1.61-1.50(m,1H).

[0669] Enantiomer 2 (132b, 93.4% ee); retention time: 3.76 min. LC-MS (ESI): m / z 365.0 [M+H] + .

[0670] Analytical methods: Column: ChiralCel OJ, 250×4.6mm ID, 5μm; Mobile phase: A, CO2, and B, MeOH (0.05% DEA); Gradient: 8min@B 40%; Flow rate: 2.0mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0671] SFC method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralCel OJ, 250×21.2mm I.D., 5μm; Mobile phase: A, CO2, and B, MeOH + 0.1% NH3·H2O; Gradient: B 40%; Flow rate: 50mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0672] Figure 21. Synthesis of cis-4-((5-ethyl-4-((2-hydroxycyclopentyl)oxy)pyrimidin-2-yl)amino)benzenesulfonamide (133)

[0673]

[0674] At 0 °C, t-BuOK (6.60 g, 58.9 mmol) was added in portions to a mixture of 2,4-dichloro-5-ethylpyrimidine (133A, 2.98 g, 19.6 mmol) and cis-cyclopentan-1,2-diol (2.00 g, 19.6 mmol) in DMSO (60 mL). The reaction mixture was stirred at room temperature for 1 hour. After stirring, the reaction mixture was poured into ice-cold saturated NH4Cl solution (60 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography to give cis-2-((2-chloro-5-ethylpyrimidin-4-yl)oxy)cyclopentan-1-ol (133B, 1.80 g, 38%) as a white solid. LC-MS (ESI): m / z 243.0 [M+H] + .

[0675] A mixture of cis-2-((2-chloro-5-ethylpyrimidin-4-yl)oxy)cyclopentan-1-ol (133B, 510 mg, 2.10 mmol), 4-aminobenzenesulfonamide (360 mg, 2.10 mmol), Cs₂CO₃ (2.05 g, 6.30 mmol), Pd(OAc)₂ (140 mg, 0.63 mmol), and Xantphos (370 mg, 0.63 mmol) in dioxane (5 mL) was purged with N₂ and then subjected to microwave conditions with stirring at 100 °C for 1.5 h. Afterward, the reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give cis-4-((5-ethyl-4-((2-hydroxycyclopentyl)oxy)pyrimidin-2-yl)amino)benzenesulfonamide (133) in racemic form, which was further separated by chiral SFC to give:

[0676] Enantiomer 1 (133a, 91.1% ee); retention time: 4.64 min. LC-MS (ESI): m / z 379.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),8.08(s,1H),7.90(d,J=8.8Hz,2H),7.71(d,J=8.8Hz,2H),7.13(s,2H),5.26(d,J=4.4Hz,1H),4.65( d,J=4.4Hz,1H),4.23(t,J=4.4Hz,1H),2.47-2.42(m,2H),2.05-1.98(m,1H),1.91-1.75(m,3H),1.71-1.55(m,2H),1.16(t,J=7.2Hz,3H).

[0677] Enantiomer 2 (133b, 90.5% ee); retention time: 5.72 min. LC-MS (ESI): m / z 379.1 [M+H] + .

[0678] Analytical methods: Column: ChiralPak IA, 250 x 4.6 mm ID, 5 μm; Mobile phase: A, CO2, and B, MeOH (0.05% DEA); Gradient: 8 min @ B 40%; Flow rate: 1.8 mL / min; Back pressure: 100 bar; Column temperature: 35 °C.

[0679] SFC method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralCel IA, 250×21.2mm I.D., 5μm; Mobile phase: A, CO2, and B, MeOH + 0.1% DEA; Gradient: B 40%; Flow rate: 50mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0680] Figure 22. Synthesis of cis-4-((5-cyclopropyl-4-((2-hydroxycyclopentyl)oxy)pyrimidin-2-yl)amino)-N-isopropylbenzenesulfonamide (134)

[0681]

[0682] At 0 °C, t-BuOK (6.60 g, 58.9 mmol) was added in portions to a mixture of 2,4-dichloro-5-iodopyrimidine (66A, 5.40 g, 19.6 mmol) and cis-cyclopentan-1,2-diol (2.00 g, 19.6 mmol) in DMSO (60 mL). The reaction mixture was stirred at room temperature for 1 hour. After stirring, the reaction mixture was poured into ice-cold saturated NH4Cl solution (60 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give cis-2-((2-chloro-5-iodopyrimidin-4-yl)oxy)cyclopentan-1-ol (134A, 4.5 g, 67%) as a white solid. LC-MS (ESI): m / z 341.0 [M+H] + .

[0683] A mixture of cis-2-((2-chloro-5-iodopyrimidin-4-yl)oxy)cyclopentan-1-ol (134A, 500 mg, 1.46 mmol), cyclopropylboronic acid (250 mg, 2.92 mmol), K₂CO₃ (607 mg, 4.40 mmol), and Pd(dppf)Cl₂ (107 mg, 0.14 mmol) in 1,4-dioxane (8 mL) and H₂O (2 mL) was degassed and backfilled three times with N₂. The reaction mixture was stirred at 100 °C under N₂ atmosphere for 5 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to giv...

Claims

1. A compound having formula II or a pharmaceutically acceptable salt thereof: Formula II in: L 1 It is a phenylene that is optionally substituted with one or more halogens; R 1 It is SO2R 10 SO2NR 11 R 12 or S(O)(NH)R 10 ; X is N or CR 13 ; Ring A is C 4-10 Cycloalkyl or a 4-10 membered heterocycle having one or more cyclic heteroatoms independently selected from O, N, and S, and ring A optionally being surrounded by one or more independently selected from deuterium, oxo, halogen, CN, C. 1-4 Alkyl groups, and C(O)(C 1-4 Substitution of alkyl groups; Q is OH; R 3 It is hydrogen, halogen, CN, C(O)NR 11 R 12 C, optionally substituted with one or more deuterium or halogens 1-6 Alkyl groups, C groups optionally substituted with one or more halogens 2-4 alkenyl, C 2-4 Alkyne group, C group optionally substituted with one or more deuterium groups 1-4 Heteroalkyl, OR A COR B COOR A NR 11 R 12 C, which can be arbitrarily replaced by CN 3-8 Carbocyclic, 4-10 membered heterocyclic, or 5-10 membered heteroaryl; R 4 It is hydrogen, halogen, C 1-6 Alkyl, or NR 11 R 12 ; in: R 10 Yes: (i) C groups optionally substituted with one or more deuterium, halogen, or 4-8 membered heterocyclic groups 1-6 Alkyl groups, (ii) C groups optionally substituted with one or more halogens 3-8 (iii) a carbocyclic group, or (iv) a phenyl group optionally surrounded by one or more C groups. 1-4 Alkyl-substituted 4-10 membered heterocyclic groups; R 11 and R 12 Each of these, in each occurrence, is independently: (i) hydrogen, (ii) a C-membered ring optionally substituted with one or more deuterium, halogen, or 4-8 membered heterocyclic groups. 1-6 Alkyl groups, (iii) C groups optionally substituted with one or more halogens 3-8 (iv) phenyl, (v) 5- or 6-membered heteroaryl, (vi) optionally surrounded by one or more C 1-4 Alkyl-substituted 4-10 membered heterocyclic groups, or (vii) nitrogen-protecting groups; or R 11 and R 12 Together with the nitrogen atoms to which they are attached, they form a mixture optionally bound by one or more C atoms. 1-4 Alkyl-substituted 4-10-membered heterocyclic groups or 5- or 6-membered heteroaryl groups; R A Each time it appears independently, it is: hydrogen, optionally selected independently by 1-3 deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-6 Alkyl group, optionally composed of 1-3 independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-8 Carbocyclic, phenyl, 5- or 6-membered heteroaryl, 4- to 10-membered heterocyclic, or oxygen-protecting group; R B Each time it appears independently, it is: hydrogen, optionally selected independently by 1-3 deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-6 Alkyl group, optionally composed of 1-3 independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-8 Carbocyclic, phenyl, 4-10 membered heterocyclic, or 5- or 6-membered heteroaryl; and R 13 It is hydrogen, F, CN, -OH, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-8 Carbon cyclic group, or 4-10 membered heterocyclic group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a monocyclic C 4-8 Cycloalkyl.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a fused, bridged, or spirobicyclic ring C. 6-10 Cycloalkyl.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a monocyclic 4-8-membered heterocycle having a cyclic heteroatom selected from O and N.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a fused, bridged, or spirobicyclic 6-10-membered heterocycle having one or two independent cyclic heteroatoms selected from O, S, and N.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula II... Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula II... Selected from: , , , , , , , , , , , or .

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound or a pharmaceutically acceptable salt thereof has the following formula II-1: Formula II-1, in: n1 and n2 are independently 0, 1, 2 or 3. Z is CR 21 R 22 , O or NR 23 , When the valence is allowed, p can be 0, 1, 2, 3, or 4. R 20 Each time it appears, it is independently of deuterium, oxo, halogen, CN, and C. 1-4 Alkyl, or C(O)(C 1-4 alkyl), Or two R 20 Forming an oxo group, or two R groups 20 Together with these inserted atoms, they form a ring structure. R 21 and R 22 Each is independently hydrogen or R 20 , Or R 21 and R 22 Together they form oxo groups or, together with the carbon atoms to which they are attached, form ring structures. Or R 21 and R 22 One and one R 20 The groups, together with these inserted atoms, form a ring structure. R 23 Is it hydrogen or R? 20 , Or R 23 And an R 20 The groups, together with these inserted atoms, form a ring structure. Where L 1 R 1 R 3 and R 4 As defined in claim 1.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein n2 is 1.

11. The compound of claim 9 or 10, or a pharmaceutically acceptable salt thereof, wherein n1 is 2.

12. The compound of claim 9 or 10 or a pharmaceutically acceptable salt thereof, wherein Z is O.

13. The compound of claim 9 or 10 or a pharmaceutically acceptable salt thereof, wherein p is 0.

14. The compound of claim 9 or 10 or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

15. The compound of claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein L in formula II or formula II-1 1 -R 1 Selected from: L in formula II or formula II-1 1 -R 1 Selected from: , 。 16. The compound of claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen, F, Cl, Br, or C optionally substituted with F and / or deuterium. 1-4 Alkyl or CN.

17. The compound of claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein R 3 Is it OR A .

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R A It is hydrogen, optionally composed of 1-3 independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

19. The compound of claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein R 3 It is COR B .

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R B It is hydrogen, optionally composed of 1-3 independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 1-4 Alkyl groups, or optionally alkyl groups independently selected from deuterium, F, CN, OH, and C. 1-4 C substituents of heteroalkyl groups 3-6 Cycloalkyl.

21. The compound of claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from: 。 22. The compound of claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein R 4 It is hydrogen.

23. The compound of claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein R 4 It is NH2.

24. A compound selected from the following, or a pharmaceutically acceptable salt thereof: 。 25. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 26. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 27. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 28. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 29. A pharmaceutical composition comprising a compound as described in any one of claims 1-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

30. Use of the compound of any one of claims 1-28 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29, in the preparation of a medicament for treating CDK2-mediated cancers.

31. The use as described in claim 30, wherein the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, and / or thyroid cancer.

32. The use as described in claim 30, wherein the cancer is selected from breast cancer of the following types: ER-positive or HR-positive, HER2-negative breast cancer; ER-positive or HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC); and inflammatory breast cancer.

33. The use as described in claim 30, wherein the cancer is selected from breast cancer that is endocrine-resistant, trastuzumab-resistant, or exhibits primary or acquired resistance to CDK4 or CDK6 inhibition.

34. The use as described in claim 30, wherein the cancer is advanced or metastatic breast cancer.

35. The use as described in claim 30, wherein the cancer is ovarian cancer.

36. The use as described in any one of claims 30-35, wherein the cancer is characterized by the amplification or overexpression of cyclin E1 and / or cyclin E2.

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