WO2022135365A1 - Disubstituted cyclopentane kinase inhibitors - Google Patents
Disubstituted cyclopentane kinase inhibitors Download PDFInfo
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- WO2022135365A1 WO2022135365A1 PCT/CN2021/139904 CN2021139904W WO2022135365A1 WO 2022135365 A1 WO2022135365 A1 WO 2022135365A1 CN 2021139904 W CN2021139904 W CN 2021139904W WO 2022135365 A1 WO2022135365 A1 WO 2022135365A1
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- WIPO (PCT)
- Prior art keywords
- optionally substituted
- alkyl
- compound
- independently
- pharmaceutically acceptable
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- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present disclosure generally relates to novel cyclopentane compounds, compositions comprising the same, methods of preparing and methods of using the same, e.g., for inhibiting cyclin-dependent kinases and/or for treating or preventing various diseases or disorders described herein.
- Cyclin-dependent kinase are a family of serine/threonine protein kinases that regulate the cell cycle progression.
- CDK2 is an essential driver for cells to transition from late G1 into S and G2 phases.
- CDK2 is activated upon binding to cyclin E.
- the cyclin E/CDK2 complex hyper-phosphorylates RB to release E2F from Rb and initiate transcription of genes necessary for G1/Stransition.
- CDK2 forms complex with Cyclin A to regulate S phase progression by activating proteins important for DNA replication and centrosome duplication, such as DNA replication licensing 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) .
- DNA replication licensing protein CDC6
- centrosome protein CP110 centrosome protein CP110
- Cyclin E1 is frequently amplified and/or overexpressed in human cancer. In high grade serous ovarian cancer, cyclin E1 amplification is detected in approximately 20%of patients and is associated with chemo 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) . Cyclin E1 amplified ovarian cancer cell lines are sensitive to reagents that either inhibit CDK2 activity or decrease cellular CDK2 protein level, suggesting CDK2 dependence in these cyclin E1 amplified cells (Au-Yeung et al.
- Estrogen receptor (ER) positive breast cancer cell lines with acquired resistance to CDK4/6 inhibitor Palbociclib has elevated cyclin E1 expression and can be re-sensitized upon knock down of CDK2 (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) .
- Cyclin E2 (CCNE2) overexpression was reported as associated with endocrine resistance in breast cancer cells and CDK2 inhibition has been reported to restore sensitivity to tamoxifen or CDK4 inhibitors in tamoxifen-resistant and CCNE2 overexpressing cells.
- 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) .
- Cyclin E amplification has also been reported as contributing 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) . Further, Cyclin E overexpression was reported to play a role in basal-like and triple negative breast cancer (TNBC) , as well as inflammatory breast cancer.
- TNBC basal-like and triple negative breast cancer
- CDK2 knock out mice are viable with minimum defects, suggesting CDK2 is not essential for normal cell proliferation (Berthet et al., CDK2 knock out mice are viable. Curr Biol. (2003) 13 (20) : 1775-85) .
- selective CDK2 inhibitors may minimize clinical toxicity while being active in treating patients with high tumor cyclinE1 and/or E2 expression.
- inhibiting CDK2 as well as other CDKs can also be clinically beneficial.
- the present disclosure relates to novel cyclopentane compounds which can inhibit CDK2, e.g., selectively over other CDKs and/or other kinases.
- the compounds and compositions herein are useful for treating various diseases or disorders, such as cancer, e.g., those characterized with amplification or overexpression of Cyclin E1 (CCNE1) and/or cyclin E2 (CCNE2) .
- Some embodiments of the present disclosure are directed to a compound of Formula I or II, or a pharmaceutically acceptable salt thereof,
- the compound of Formula I can have a sub-formula of I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c as defined herein.
- the compound of Formula II can have a subformula of II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b, as defined herein.
- the present disclosure also provides specific compounds selected from the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof.
- the present disclosure provides a pharmaceutical composition comprising one or more compounds of the present disclosure and optionally a pharmaceutically acceptable excipient.
- the pharmaceutical composition can be typically formulated for oral administration.
- the present disclosure also provides a method of inhibiting CDK activity such as CDK2 activity in a subject or biological sample.
- the method comprises contacting the subject or biological sample with an effective amount of one or more compounds of the present disclosure, e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos.
- Formula I e.
- the present disclosure provides a method of treating or preventing a CDK-mediated disease or disorder in a subject in need thereof.
- the method comprises administering to the subject an effective amount of one or more compounds of the present disclosure or the pharmaceutical composition herein.
- the method comprises administering to the subject an effective amount of a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
- a compound of Formula I e.g., I-A, I-B, I-C, I-D
- the present disclosure also provides a method of treating or preventing cancer in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I- C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos.
- a compound of the present disclosure e.g., a compound of Formula I
- the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
- 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 (i.e., gastric) cancer, thyroid cancer, and combinations thereof.
- the cancer is breast cancer selected from ER-positive/HR-positive, HER2-negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC) ; and inflammatory breast cancer.
- the cancer is breast cancer.
- the cancer is breast cancer selected from endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
- the cancer is advanced or metastatic breast cancer.
- the cancer is ovarian cancer.
- the administering in the methods herein is not limited to any particular route of administration.
- the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
- the administering is orally.
- the administering is a parenteral injection, such as an intraveneous injection.
- Compounds of the present disclosure can be used as a monotherapy or in a combination therapy.
- one or more compounds of the present disclosure can be administered as the only active ingredient (s) .
- the method herein further comprises administering to the subject an additional therapeutic agent, such as additional anticancer agents described herein.
- the present disclosure provides compounds and compositions that are useful for inhibiting CDKs such as CDK2 and/or treating or preventing various diseases or disorders described herein, e.g., cancer.
- the compounds herein can typically inhibit CDK2.
- the compounds herein can selectively inhibit CDK2 over other CDKs, for example, over CDK1, with a selectivity of more than 10-fold, and up to about 30-fold and beyond.
- the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:
- L 1 is a bond, NH, O, optionally substituted C 1-4 alkylene, optionally substituted C 1-4 heteroalkylene, or
- R 1 is an optionally substituted 5-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl (e.g., 5-or 6-membered heteroaryl, or 8-10 membered bicyclic heteroaryl) ;
- X is NR 10 or O
- Y is a bond, O, NR 10 , optionally substituted C 1-4 alkylene, or optionally substituted C 1-4 heteroalkylene;
- R 2 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or NR 11 R 12 ;
- R 10 at each occurrence is independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl;
- each of R 11 and R 12 is independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl; or a nitrogen protecting group; or R 11 and R 12 , together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl.
- the compound of Formula I (including any of the applicable sub-formulae as described herein) comprises at least two asymmetric centers.
- the compound of Formula I exists predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) .
- the compound of Formula I can also exist in a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
- the other enantiomer of the as-drawn stereoisomer of the compound of Formula I (including any of the applicable sub-formulae as described herein) is also provided, which can exist in a substantially pure form or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
- the other enantiomer, Formula I-EN2 can exist as an individual enantiomer substantially free (e.g., with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount) of the as-drawn enantiomer of the compound of Formula I:
- L 1 in Formula I is a bond, which means that R 1 is directly linked to the pyrazole ring, and Formula I can be represented by Formula I-A:
- R 1 , R 2 , X, and Y include any of those described herein in any combination.
- L 1 in Formula I is NH
- Formula I can be represented by Formula I-B:
- R 1 , R 2 , X, and Y include any of those described herein in any combination.
- R 1 is typically an optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.
- R 1 is an optionally substituted imidazole.
- the compound of Formula I can be characterized as having Formula I-1:
- R 20 and R 21 are each independently OH, halogen, CN, R g1 , OR g1 , C (O) R g1 , C (O) OR g1 , S (O) R g1 , S (O) 2 R g1 , S (O) 2 NR a R b , C (O) NR a R b , NR a R b or S (O) (NR c ) R g1 ; or R 20 and R 21 , together with the intervening atoms, form an optionally substituted 4-8 membered ring, e.g., an optionally substituted phenyl or optionally substituted 5-or 6-membered heteroaryl;
- R a and R b are each independently R g1 , C (O) R g1 , C (O) OR g1 , or C (O) NR g1 R g1 , or a nitrogen protecting group; or R a and R b , together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;
- R c is hydrogen or C 1-4 alkyl
- R g1 at each occurrence is independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl, and
- R 2 , X, and Y include any of those described herein in any combination.
- R 20 and R 21 are each independently hydrogen, OH, halogen, CN, R g2 , C (O) R g2 , or S (O) 2 R g2 ,
- R g2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, phenyl, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, or 5-or 6-membered heteroaryl is independently optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , oxo (as valency permits) , OH, CN, C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , phenyl optionally substituted with one or more (e.g., 1, 2,
- R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and
- R s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C 1-4 alkoxy optionally substituted with 1-3 F.
- R 20 and R 21 are each independently hydrogen, halogen, CN, C 1-4 alkyl, C (O) -C 1-4 alkyl, S (O) 2 -C 1-4 alkyl, C 1-4 alkyl substituted with 1-3 fluorine, C 1-4 heteroalkyl, C 1-4 heteroalkyl substituted with 1-3 fluorine, phenyl, pyridyl, or pyrazolyl, wherein the phenyl, pyridyl, or pyrazolyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more
- R 20 and R 21 are each independently hydrogen, C 1-4 alkyl, C (O) -C 1-4 alkyl, S (O) 2 -C 1-4 alkyl, C 1-4 alkyl substituted with 1-3 fluorine, C 1-4 heteroalkyl, C 1-4 heteroalkyl substituted with 1-3 fluorine, or a group selected from the following:
- R 20 and R 21 can be hydrogen, for example, R 20 is hydrogen or R 21 is hydrogen.
- R 20 and R 21 together with the intervening atoms, can also form an optionally substituted phenyl or an optionally substituted 5-or 6-membered heteroaryl.
- R 20 and R 21 together with the intervening atoms, can form a phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R g2 , C (O) R g2 , or S (O) 2 R g2 ,
- R g2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, phenyl, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, or 5-or 6-membered heteroaryl is independently optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , oxo (as valency permits) , OH, CN, C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , phenyl optionally substituted with one or more (e.g., 1, 2,
- R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and
- R s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C 1-4 alkoxy optionally substituted with 1-3 F.
- R 20 and R 21 together with the intervening atoms, can form a phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one or more (e.g., 1, or 2) substituents each independently halogen (e.g., F or Cl) , CN, OH, C (O) -C 1-4 alkyl, S (O) 2 -C 1-4 alkyl, C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , 4-7 membered heterocycly
- R 20 and R 21 together with the intervening atoms, can form a phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one or more (e.g., 1, or 2) substituents each independently selected from F, Cl, methyl, ethyl, CH 3 OCH 2 , methoxy, CH 3 S (O) 2 CH 2 , CH 3 CO, oxetanyl, CH 3 CF 2 , and isopropyl.
- substituents each independently selected from F, Cl, methyl, ethyl, CH 3 OCH 2 , methoxy, CH 3 S (O) 2 CH 2 , CH 3 CO, oxetanyl, CH 3 CF 2 , and isopropyl.
- the compound of Formula I can be characterized as having Formula I-B as described herein.
- R 1 can be an optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.
- R 1 is an optionally substituted 6-membered heteroaryl, such as pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
- R 1 can be pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h1 , OR h1 , C (O) R h1 , C (O) H, C (O) OR h1 , COOH, S (O) R h1 , S (O) 2 R h1 , S (O) 2 NR a R b , C (O) NR a R b , NR a R b or S (O) (NR c ) R h1 ,
- R a and R b are each independently hydrogen, R h1 , C (O) H, C (O) R h1 , C (O) OR h1 , CONH 2 , C (O) NHR h1 , or C (O) NR h1 R h1 , or a nitrogen protecting group; or R a and R b , together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;
- R c is hydrogen or C 1-4 alkyl
- R h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- R 1 can be pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h2 or OR h2 ,
- R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R pheny
- R 1 can be selected from:
- pyridyl, pyridazinyl, or pyrazinyl is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R h3 or OR h3 , wherein R h3 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , or C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- the pyridyl, pyridazinyl, or pyrazinyl is substituted with one or two substituents each independently methyl, F, Cl, CN,
- R 1 can be a 5, 6-bicyclic or 6, 6-bicyclic heteroaryl having 1-4 ring heteroatoms independently selected from N, O, and S, which can be optionally substituted.
- the 5, 6-bicyclic or 6, 6-bicyclic heteroaryl can be optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h1 , OR h1 , C (O) R h1 , C (O) H, C (O) OR h1 , COOH, S (O) R h1 , S (O) 2 R h1 , S (O) 2 NR a R b , C (O) NR a R b , NR a R b or S (O) (NR c ) R h1 ,
- substituents each independently OH, halogen, CN, R h1 , OR h1 , C (O) R h1 , C (O) H, C (O) OR h1 , COOH, S (O) R h1 , S (O) 2 R h1 , S (O) 2 NR a
- R a and R b are each independently hydrogen, R h1 , C (O) H, C (O) R h1 , C (O) OR h1 , CONH 2 , C (O) NHR h1 , or C (O) NR h1 R h1 , or a nitrogen protecting group; or R a and R b , together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;
- R c is hydrogen or C 1-4 alkyl
- R h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- R 1 can be selected from:
- each of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R h2 or OR h2 , wherein R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more substituents (e.g., 1, 2, or 3) each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R pheny
- R 1 can be selected from:
- each of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R h3 or OR h3 , wherein R h3 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , and C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- the foregoing bicyclic heteroaryl is substituted with one or two substituents each independently methyl, methyl substituted with 1-3 F (e.g., CF 3 ) , F, Cl, CN,
- R 1 can be selected from:
- R 1 can be In some preferred embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R 1 can be In some preferred embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R 1 can be In some embodiments according to Formula I-B, R 1 can be wherein R 110 is halogen (e.g., F or Cl) or optionally substituted C 1-3 alkyl, such as those substituted with 1-3 fluorine, such as CF 3 .
- R 110 is halogen (e.g., F or Cl) or optionally substituted C 1-3 alkyl, such as those substituted with 1-3 fluorine, such as CF 3 .
- L 1 in Formula I can also be and Formula I can be represented by Formula I-C:
- R 1 , R 2 , X, and Y include any of those described herein in any combination.
- R 1 for Formula I-C can include any of those described herein above in connection with Formula I-A or I-B.
- L 1 in Formula I can also be an optionally substituted C 1-4 alkylene.
- L 1 in Formula I can also be an optionally substituted C 1-4 heteroalkylene.
- X is O.
- X in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , X can be NR 10 , wherein R 10 is defined herein.
- R 10 is defined herein.
- X can be NH.
- Y is NH
- Y in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , Y can be a bond, in which case, R 2 is bonded directly with the carbonyl group.
- Y in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , Y can be O.
- Y in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , Y can also be an optionally substituted C 1-4 alkylene, such as CH 2 .
- Y in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , Y can also be an optionally substituted C 1-4 heteroalkylene.
- Formula I in Formula I can be for example, in some embodiments, the compound of Formula I, such as I-A, I-B, I-C, or I-1, can be characterized as having a structure according to the following subformulae I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-1-a, I-1-b, I-1-c, I-C-1, I-C-2, or I-C-3:
- R 1 , R 2 , R 20 , and R 21 can be any of those defined herein in connection with Formula I, including any applicable subformulae, in any combinations.
- R 2 can be hydrogen.
- R 2 can be an optionally substituted C 1-6 alkyl.
- R 2 can be an optionally substituted C 3-8 carbocyclyl.
- R 2 can be an optionally substituted 4-10 membered heterocyclyl.
- R 2 can be an optionally substituted phenyl.
- R 2 can be an optionally substituted 5-10 membered heteroaryl.
- R 2 can be NR 11 R 12 , wherein R 11 and R 12 are defined herein.
- R 2 can be a C 1-6 alkyl, such as isopropyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, oxo (as valency permits) , C 1-4 heteroalkyl optionally substituted with 1-3 F, C 3-6 cycloalkyl, or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, wherein the C 3-6 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with halogen (e.g., F or Cl) , OH, CN, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, or C
- halogen e.g., F or Cl
- R 2 in Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) , R 2 can be a C 3-6 cycloalkyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 heteroalkyl optionally substituted with 1-3 F.
- substituents each independently F, OH, CN, oxo (as valency permits)
- C 1-4 alkyl optionally substituted with 1-3 F
- C 1-4 heteroalkyl optionally substituted with 1-3 F.
- R 2 can be a 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , R s3 , OR s3 , or C (O) R s3 , wherein R s3 at each occurrence is independently C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4 , C 3-6 cycloalkyl optionally substituted with one or more (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) , R 2 can be a 4-8 membered
- R 2 in any of the embodiments described herein, unless specified or otherwise contrary from context, in Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) , R 2 can be selected from:
- R 2 has one or more asymmetric centers.
- the present disclosure is not limited to any particular stereoisomer.
- the compound of Formula I having such R 2 groups can also be enriched in one or more of the stereoisomers.
- the compound of Formula I e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a
- R 2 selected from the following groups with the configuration (s) as drawn below:
- the compound in Formula I, with respect to R 2 groups, can exist predominantly as the as-drawn stereoisomer shown above, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) .
- the compound of Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) can also exist in a mixture of stereoisomers in any molar ratio, including 1: 1 ratio of a pair of enantiomers of the applicable R 2 groups.
- R 2 in Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) , R 2 can be isopropyl or cyclopropyl.
- Formula II e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a
- Formula II e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a
- the present disclosure provides a compound of Formula II, or a pharmaceutically acceptable salt thereof:
- A is an optionally substituted 5-membered or 6-membered heteroaryl, optionally substituted 8-10 membered bicyclic heteroaryl,
- L 2 is a bond, O, optionally substituted C 1-4 alkylene, optionally substituted C 1-4 heteroalkylene, NH,
- R 3 is L 3 - (phenyl) , L 3 - (5-10 membered heterocyclyl) or L 3 - (5-10 membered heteroaryl) , wherein the phenyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl (e.g., 5-or 6-membered heteroaryl, or 8-10 membered bicyclic heteroaryl) is optionally substituted, and L 3 is a bond, an optionally substituted C 1-4 alkylene, or optionally substituted C 1-4 heteroalkylene;
- X is NR 10 or O
- Y is a bond, O, NR 10 , optionally substituted C 1-4 alkylene, or optionally substituted C 1-4 heteroalkylene;
- R 2 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or NR 11 R 12 ;
- R 10 at each occurrence is independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl;
- each of R 11 and R 12 is independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl; or a nitrogen protecting group; or R 11 and R 12 , together with the nitrogen atom they are attached, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl.
- the compound of Formula II (including any of the applicable sub-formulae as described herein) comprises at least two asymmetric centers.
- the compound of Formula II exists predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) .
- the compound of Formula II can also exist in a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
- the other enantiomer of the as-drawn stereoisomer of the compound of Formula II (including any of the applicable sub-formulae as described herein) is also provided, which can exist in a substantially pure form or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
- the other enantiomer Formula II-EN2 can exist as an individual enantiomer substantially free (e.g., with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount) of the as-drawn enantiomer of the compound of Formula II:
- variables for Formula II-EN2 can be the same as those defined herein for Formula II.
- a in Formula II can be an optionally substituted 5-membered heteroaryl, such as an optionally substituted imidazole.
- the compound of Formula II can be characterized as having a Formula II-A:
- L 2 , R 3 , R 2 , X, and Y include any of those described herein in any combination.
- L 2 in Formula II-A is NH or and the compound of Formula II-A can be characterized as having a Formula II-A-1 or II-A-2:
- R 3 , R 2 , X, and Y include any of those described herein in any combination.
- L 2 in Formula II-A can also be a bond. In some embodiments, L 2 in Formula II-A can also be O. In some embodiments, L 2 in Formula II-A can also be an optionally substituted C 1-4 alkylene, such as CH 2 . In some embodiments, L 2 in Formula II-A can also be an optionally substituted C 1-4 heteroalkylene. In some embodiments, L 2 in Formula II-A can also be
- R 3 can be L 3 - (5-10 membered heteroaryl) , wherein the 5-10 membered heteroaryl is optionally substituted.
- L 3 is a bond.
- L 3 can be an optionally substituted C 1-4 alkylene.
- L 3 can be an optionally substituted C 1-4 heteroalkylene.
- R 3 can be an optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, such as pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
- R 3 can be pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R h1 , OR h1 , C (O) R h1 , C (O) H, C (O) OR h1 , COOH, S (O) R h1 , S (O) 2 R h1 , S (O) 2 NR a R b , C (O) NR a R b , NR a R b or S (O) (NR c ) R h1 , wherein R a and R b are each independently hydrogen, R h1 , C (O) H, C (O) R h1 , C (O) OR h1 , each of which is optionally substituted with one or more (e.g., 1 or 2) substituents
- R c is hydrogen or C 1-4 alkyl
- R h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- R 3 can be pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R h2 or OR h2 ,
- R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R pheny
- R 3 can be selected from:
- pyridyl, pyridazinyl, or pyrazinyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h3 or OR h3 , wherein R h3 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- the pyridyl, pyridazinyl, or pyrazinyl is substituted with one or two substituents each independently methyl, F, Cl, CN,
- R 3 can be an optionally substituted 5, 6-bicyclic or 6, 6-bicyclic heteroaryl having 1-4 ring heteroatoms independently selected from N, O, and S.
- the 5, 6-bicyclic or 6, 6-bicyclic heteroaryl can be optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h1 , OR h1 , C (O) R h1 , C (O) H, C (O) OR h1 , COOH, S (O) R h1 , S (O) 2 R h1 , S (O) 2 NR a R b , C (O) NR a R b , NR a R b or S (O) (NR c ) R h1 , wherein R a and R b are each independently hydrogen, R h1 , C (O) H, C (O) R h1 , C (O) OR h1 , CONH 2 , C (O) NHR h1 , or C (O) NR h1 R h1 , or a
- R c is hydrogen or C 1-4 alkyl
- R h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- R 3 can be selected from:
- each of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R h2 or OR h2 ,
- R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2 , phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R pheny
- R 3 can be selected from:
- each of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h3 or OR h3 ,
- R h3 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , and C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- R 3 can be selected from:
- each of the foregoing bicyclic heteroaryls is substituted with one or two substituents each independently methyl, F, Cl, CN,
- R 3 can be selected from:
- R 3 can be L 3 - (phenyl) or L 3 - (5-10 membered heteroaryl) , wherein the phenyl or 5-10 membered heteroaryl is optionally substituted.
- L 3 is a bond.
- L 3 is an optionally substituted C 1-4 alkylene.
- L 3 is an optionally substituted C 1-4 heteroalkylene.
- R 3 can be -CH 2 -R 30 or R 30 , wherein R 30 is an optionally substituted phenyl or optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.
- R 30 is an optionally substituted phenyl or optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.
- the compound of Formula II-A-2 can be characterized as having Formula II-A-2a or II-A-2b:
- R 30 , R 2 , X, and Y include any of those described herein in any combination.
- R 30 can be selected from:
- substituents each independently OH, halogen, CN, R h2 , S (O) 2 R h2 or OR h2 ,
- R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- R 30 can be selected from:
- substituents each independently OH, halogen, CN, R h2 , S (O) 2 R h2 or OR h2 ,
- R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
- C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1 , wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- R 30 can be selected from:
- each of which can be substituted with one or two substituents each independently methyl, F, Cl, methyl, ethyl, CH 3 OCH 2 , methoxy, CH 3 S (O) 2 , CH 3 S (O) 2 CH 2 , CH 3 CO, oxetanyl, tetrahydrofuranyl, CH 3 CF 2 , and isopropyl.
- L 2 -R 3 in Formula II-A-2 can be selected from:
- a in Formula II can be an optionally substituted 6-membered heteroaryl having 1-3 ring nitrogen atoms, such as an optionally substituted pyrazine or optionally substituted triazine.
- the compound of Formula II can be characterized as having a Formula II-B or II-C:
- pyrazine or triazine is optionally substituted with a substituent selected from F, Cl, CN, OH, methyl, methoxy, or OCD 3 , and
- L 2 , R 3 , R 2 , X, and Y include any of those described herein in any combination.
- L 2 is typically NH.
- R 3 is typically an optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-10 membered heterocycles.
- R 3 can be selected from:
- substituents each independently OH, halogen, CN, R h1 , OR h1 , C (O) R h1 , C (O) H, C (O) OR h1 , COOH, S (O) R h1 , S (O) 2 R h1 , S (O) 2 NR a R b , C (O) NR a R b , NR a R b or S (O) (NR c ) R h1 , provided that at least one of the substituents is S (O) (NR c ) R h1 , S (O) 2 R h1 , S (O) 2 NR a R b or C (O) NR a R b , wherein R a and R b are each independently hydrogen, R h1 , C (O) H, C (O) R h1 , C (O) OR h1 , COOH, S (O) R h1 , S (O
- R c is hydrogen or C 1-4 alkyl
- R h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- R 3 can be selected from:
- R j is OH, halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl, and
- R h2 is C 1-4 alkyl or C 3-6 cycloalkyl
- each of the C 1-4 alkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl is optionally substituted with 1-3 F,
- R a , R b , and R c are defined herein in connection with R 3 in Formula II-B or II-C.
- the NR a R b is NH 2 .
- R 3 can be selected from:
- a in Formula II can also be an optionally substituted 8-10 membered bicyclic heteroaryl, such as an optionally substituted 5, 6-bicyclic heteroaryl having 1-4 ring nitrogen atoms.
- the ring that immediately connected to the cyclopentane ring in Formula II is an imidazole or pyrazole ring, whereas the ring distal to the cyclopentane ring is typically a pyridine, pyrimidine, pyridazine, pyrazine, or triazine ring.
- a in Formula II can be selected from:
- the compound of Formula II can be characterized as having a formula II-D:
- n 0 or 1
- R 100 is F, Cl, CN, OH, methyl, methoxy, or OCD 3 and
- L 2 , R 3 , R 2 , X, and Y include any of those described herein in any combination. It should be understood that when n is 1, R 100 may be attached at either the 5-member ring or the 6-member ring of the bicyclic heteroaryl, although preferably, the attach point is on the 6-membered ring.
- the compound of Formula II can be characterized as having a formula II-E:
- n 0 or 1
- R 100 is F, Cl, CN, OH, methyl, methoxy, or OCD 3 and
- L 2 , R 3 , R 2 , X, and Y include any of those described herein in any combination. It should be understood that when n is 1, R 100 may be attached at either the 5-member ring or the 6-member ring of the bicyclic heteroaryl, although preferably, the attach point is on the 6-membered ring.
- the compound of Formula II can be characterized as having a formula II-F:
- n 0 or 1
- R 100 is F, Cl, CN, OH, methyl, methoxy, or OCD 3 and
- L 2 , R 3 , R 2 , X, and Y include any of those described herein in any combination. It should be understood that when n is 1, R 100 may be attached at either the 5-member ring or the 6- member ring of the bicyclic heteroaryl, although preferably, the attach point is on the 6-membered ring.
- the compound of Formula II can be characterized as having a formula II-G:
- n 0 or 1
- R 100 is F, Cl, CN, OH, methyl, methoxy, or OCD 3 and
- L 2 , R 3 , R 2 , X, and Y include any of those described herein in any combination. It should be understood that when n is 1, R 100 may be attached at either the 5-member ring or the 6-member ring of the bicyclic heteroaryl, although preferably, the attach point is on the 6-membered ring.
- the compound of Formula II can be characterized as having a formula II-H:
- n 0 or 1
- R 100 is F, Cl, CN, OH, methyl, methoxy, or OCD 3 and
- L 2 , R 3 , R 2 , X, and Y include any of those described herein in any combination. It should be understood that when n is 1, R 100 may be attached at either the 5-member ring or the 6-member ring of the bicyclic heteroaryl, although preferably, the attach point is on the 6-membered ring.
- L 2 is typically NH.
- R 3 can typically be represented by the formula: C (R 40 ) (R 41 ) -R 42 , wherein:
- R 40 and R 41 are independently hydrogen, deuterium, or methyl, or R 40 and R 41 , together with the carbon they are both attached to, form an optionally substituted C 3-6 cycloalkyl or optionally substituted 4-8 membered heterocyclyl, and
- R 42 is an optionally substituted phenyl or optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.
- R 40 and R 41 are the same, and both are hydrogen, deuterium, or methyl.
- R 40 is hydrogen, and R 41 is deuterium or methyl.
- R 40 and R 41 together with the carbon they are both attached to, form a cyclopropyl.
- R 42 can be selected from:
- R a and R b are each independently hydrogen, R h1 , C (O) H, C (O) R h1 , C (O) OR h1 , CONH 2 , C (O) NHR h1 , or C (O) NR h1 R h1 , or a nitrogen protecting group; or R a and R b , together with the nitrogen atom they are attached
- R c is hydrogen or C 1-4 alkyl
- R h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- R 42 can be selected from:
- substituents each independently OH, halogen, CN, C 1-4 alkyl, or C 1-4 alkoxy, wherein the C 1-4 alkyl or C 1-4 alkoxy is optionally substituted with 1-3 F.
- R 42 can be selected from:
- substituents each independently F, Cl, CH 3 OCH 2 , methyl, ethyl, or methoxy.
- R 3 can be selected from:
- X can be O or NH.
- Y can be O, NH, a bond or CH 2 .
- R 2 can be hydrogen.
- R 2 can be an optionally substituted C 1-6 alkyl.
- R 2 can be an optionally substituted C 3-8 carbocyclyl.
- R 2 can be an optionally substituted 4-10 membered heterocyclyl.
- R 2 can be an optionally substituted phenyl.
- R 2 can be an optionally substituted 5-10 membered heteroaryl.
- R 2 can be NR 11 R 12 , wherein R 11 and R 12 are defined herein.
- R 2 in Formula II (e.g., Formula II-A to II-H) , can be a C 1-6 alkyl, such as isopropyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, oxo (as valency permits) , C 1-4 heteroalkyl optionally substituted with 1-3 F, C 3-6 cycloalkyl, or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, wherein the C 3-6 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with halogen (e.g., F or Cl) , OH, CN, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 heteroalkyl optionally substituted with 1-3 F.
- halogen e.g., F or Cl
- R 2 in Formula II (e.g., Formula II-A to II-H) , can be a C 3-6 cycloalkyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 heteroalkyl optionally substituted with 1-3 F.
- substituents each independently F, OH, CN, oxo (as valency permits)
- C 1-4 alkyl optionally substituted with 1-3 F
- C 1-4 heteroalkyl optionally substituted with 1-3 F.
- R 2 in Formula II (e.g., Formula II-A to II-H) , can be a 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , R s3 , OR s3 , or C (O) R s3 , wherein R s3 at each occurrence is independently C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4 , C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4 , C 3- 6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4 , or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms
- R 2 in any of the embodiments described herein, unless specified or otherwise contrary from context, in Formula II (e.g., Formula II-A to II-H) , R 2 can be selected from:
- R 2 has one or more asymmetric centers.
- the present disclosure is not limited to any particular stereoisomer.
- the compound of Formula II having such R 2 groups can also be enriched in one or more of the stereoisomers.
- the compound of Formula II e.g., Formula II-A to II-H
- R 2 selected from the following groups with the configuration (s) as drawn below:
- the compound in Formula II, with respect to R 2 groups, can exist predominantly as the as-drawn stereoisomer shown above, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) .
- the compound of Formula II e.g., Formula II-A to II-H
- the present disclosure also provide a compound selected from Table 1A below, or a pharmaceutically acceptable salt thereof:
- the present disclosure also provide a compound selected from Table 1B below, or a pharmaceutically acceptable salt thereof:
- Compounds of Table 1A and 1B can exist in various stereoisomeric forms, such as individual isomer, an individual enantiomer and/or diastereomer, as applicable, or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
- a compound shown Table 1A or 1B when applicable, can exist as the as-drawn enantiomer substantially free (e.g., with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount) of the other enantiomer.
- a compound shown Table 1A or 1B can also exist as a mixture of stereoisomers in any ratio, such as a racemic mixture.
- the present disclosure also provide a compound selected from the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof.
- the genus of compounds described herein also excludes any specifically known single compounds prior to this disclosure. In some embodiments, to the extent applicable, any sub-genus or species of compounds prior to this disclosure that are entirely within a genus of compounds described herein can also be excluded from such genus herein.
- the compounds of the present disclosure can be readily synthesized by those skilled in the art in view of the present disclosure. Similar synthetic processes can also be found in WO2020/157652, the content of which is herein incorporated by reference in its entirety.
- the reagents for preparing the compounds herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of such reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) , Sigma (St. Louis, Missouri, USA) .
- Certain embodiments are directed to a pharmaceutical composition comprising one or more compounds of the present disclosure.
- the pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient.
- the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos.
- Formula I e.g., I-A, I-B, I-C, I-D, I-A-1, I
- Non-limiting suitable excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference) , which discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
- the pharmaceutical composition can include any one or more of the compounds of the present disclosure.
- the pharmaceutical composition comprises a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos.
- Formula I e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B
- the pharmaceutical composition can comprise a therapeutically effective amount (e.g., for treating breast cancer or ovarian cancer) of a compound selected from the specific compounds disclosed in Table 1A herein, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition can comprise a therapeutically effective amount (e.g., for treating breast cancer or ovarian cancer) of a compound selected from the specific compounds disclosed in Table 1B herein, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition can comprise a therapeutically effective amount (e.g., for treating breast cancer or ovarian cancer) of a compound selected from the compounds according to Compound Nos. I-IX herein, for example, Compound No. I, II, or III, or a pharmaceutically acceptable salt thereof.
- composition herein can be formulated for delivery via any of the known routes of delivery, which include but not limited to administering orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally or parenterally.
- the pharmaceutical composition can be formulated for oral administration.
- the oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non- aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
- Excipients for the preparation of compositions for oral administration are known in the art.
- Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1, 3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl
- the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection) .
- the parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion.
- Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1, 3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.
- Compounds of the present disclosure can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, e.g., in combination with an additional anticancer therapeutic agent, such as mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like.
- an additional anticancer therapeutic agent such as mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and
- one or more compounds of the present disclosure can be used in combination with one or more targeted agents, such as inhibitors of PI3 kinase, mTOR, PARP, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, Src/Abl, RTK/Ras, Myc, Raf, PDGF, AKT, c-Kit, erbB, CDK4/CDK6, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1, EZH2 or Hsp90, or immunomodulatory agents, such as PD-1 or PD-L1 antagonists, OX40 agonists or 4-1BB agonists.
- targeted agents such as inhibitors of PI3 kinase, mTOR, PARP, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, S
- one or more compounds of the present disclosure can be used in combination with a standard of care agent, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole or trastuzumab.
- a standard of care agent such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole or trastuzumab.
- Suitable additional anticancer therapeutic agent include any of those known in the art, such as those approved for the appropriate cancer by a regulatory agency such as the U.S. Food and Drug Administration.
- suitable additional anticancer therapeutic agents also include those described in WO2020/157652, US2018/0044344, WO2008/122767, etc., the content of each of
- compounds of the present disclosure or pharmaceutical compositions herein can be administered to the subject either concurrently or sequentially in any order with such additional therapeutic agents.
- the pharmaceutical composition can comprise one or more compounds of the present disclosure and the one or more additional therapeutic agents in a single composition.
- the pharmaceutical composition comprising one or more compounds of the present disclosure can be included in a kit which also comprises a separate pharmaceutical composition comprising the one or more additional therapeutic agents.
- the pharmaceutical composition can include various amounts of the compounds of the present disclosure, depending on various factors such as the intended use and potency and selectivity of the compounds.
- the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure.
- the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient.
- a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, such as breast cancer or ovarian cancer, which can depend on the recipient of the treatment, the disorder, condition or disease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.
- compounds of the present disclosure have various utilities.
- compounds of the present disclosure can be used as therapeutic active substances for the treatment and/or prophylaxis of a CDK2-mediated disease or disorder.
- some embodiments of the present disclosure are also directed to methods of using one or more compounds of the present disclosure or pharmaceutical compositions herein for treating or preventing a CDK2-mediated disease or disorder in a subject in need thereof, such as for treating cancer in a subject in need thereof.
- the present disclosure provides a method of inhibiting abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition described herein.
- the abnormal cell growth is cancer characterized by amplification or overexpression of cyclin E1 (CCNE1) and/or cyclin E2 (CCNE2) .
- the subject is identified as having a cancer characterized by amplification or overexpression of CCNE1 and/or CCNE2.
- the present disclosure also provides a method of inhibiting CDK activity in a subject or biological sample.
- the present disclosure provides a method of inhibiting CDK2 activity in a subject or biological sample, which comprises contacting the subject or biological sample with an effective amount of the compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein
- the present disclosure provides a method of treating or preventing a CDK mediated, in particular CDK2-mediated disease or disorder in a subject in need thereof.
- the method comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound
- the CDK2-mediated disease or disorder is cancer.
- the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2
- the present disclosure also provides a method of treating or preventing cancer in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos.
- a compound of the present disclosure e.g., a compound of Formula I
- the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
- the subject is identified as having a cancer characterized by amplification or overexpression of CCNE1 and/or CCNE2.
- 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 (i.e., gastric) cancer, thyroid cancer, and combinations thereof.
- the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer and/or stomach cancer.
- 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.
- the breast cancer can be endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
- the breast cancer can be advanced or metastatic breast cancer.
- the breast cancer described herein is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
- the cancer is ovarian cancer.
- the ovarian cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
- the cancer is blood cancer such as leukemia.
- the cancer is chronic lymphocytic leukemia, such as relapsed or refractory Chronic Lymphocytic Leukemia (CLL) .
- CLL Chronic Lymphocytic Leukemia
- the cancer is acute myeloid leukemia. In some embodiments of the methods herein, the cancer is relapsed or refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes.
- the cancer herein can be characterized by amplification or overexpression of CCNE1 and/or CCNE2.
- the present disclosure also provides a method of treating breast cancer in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos.
- a compound of the present disclosure e.g., a compound of Formula
- 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.
- the breast cancer is selected from endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
- the breast cancer is advanced or metastatic breast cancer.
- the breast cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
- the present disclosure also provides a method of treating ovarian cancer in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt
- the present disclosure also provides a method of treating leukemia in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof
- the present disclosure also provides a method of treating chronic lymphocytic leukemia, such as relapsed or refractory Chronic Lymphocytic Leukemia (CLL) , in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1
- the present disclosure also provides a method of treating acute myeloid leukemia, such as relapsed or refractory Acute Myeloid Leukemia, in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the specific compounds
- the present disclosure also provides a method of treating Myelodysplastic Syndromes in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a
- the administering in the methods herein is not limited to any particular route of administration.
- the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
- the administering is orally.
- the administering is a parenteral injection, such as an intraveneous injection.
- Compounds of the present disclosure can be used as a monotherapy or in a combination therapy.
- one or more compounds of the present disclosure can be administered as the only active ingredient (s) .
- one or more compounds of the present disclosure can also be co-administered with an additional therapeutic agent, either concurrently or sequentially in any order, to the subject in need thereof.
- the additional therapeutic agent can typically be an additional anticancer therapeutic agent, such as mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like.
- additional anticancer therapeutic agent such as mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and
- the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor, a SERD or a SERM.
- one or more compounds of the present disclosure can 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 immunomodulatory agents, such as PD-1 or PD-L1 antagonists, OX40 agonists or 4-1BB agonists.
- targeted agents such as inhibitors of PI3 kinase, mTOR, PARP, I
- one or more compounds of the present disclosure can be administered administered in combination with a standard of care agent, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole or trastuzumab.
- a standard of care agent such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole or trastuzumab.
- Suitable additional anticancer therapeutic agent include any of those known in the art, such as those approved for the appropriate cancer by a regulatory agency such as the U.S. Food and Drug Administration.
- suitable additional anticancer therapeutic agents also include those described in WO2020/157652, US2018/0044344, WO2008/122767, etc., the contents of each
- Dosing regimen including doses for the methods described herein can vary and be adjusted, which can depend on the recipient of the treatment, the disorder, condition or disease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.
- variable moiety herein can be the same or different as another specific embodiment having the same identifier.
- Suitable groups for the variables in compounds of Formula I, or a subformula thereof, as applicable, are independently selected.
- Non-limiting useful groups for the variables in compounds of Formula I, or a subformula thereof, as applicable, include any of the respective groups, individually or in any combination, as shown in the specific compounds described in Table 1A or 1B herein.
- compounds of Formula I can include a R 1 group according to any of the R 1 groups shown in the specific compounds described in Table 1A or 1B herein, without regard to the other variables shown in the specific compounds.
- compounds of Formula I can include a R 1 group according to any of the R 1 groups shown in the specific compounds described in Table 1A or 1B herein in combination at least one other variable (e.g, L 1 ) according to the specific compounds described in Table 1A or 1B herein, wherein the R 1 and at least one other variable can derive from the same compound or a different compound. Any of such combinations are contemplated and within the scope of the present disclosure.
- any one or more of L 1 , R 1 , R 2 , X, and Y of Formula I e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c
- the definition of any one or more of L 1 , R 1 , R 2 , X, and Y of Formula I can be combined with the definition of any one or more of the other (s) of L 1 , R 1 , R 2 , X, and Y, as applicable, and the resulted compounds from the combination are within the scope of the present disclosure.
- Similar combinations of variables are also contemplated in connection with Formula II.
- Compounds described herein can comprise one or more asymmetric centers in addition to those shown in Formula I or II, and can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
- the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
- Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
- HPLC high performance liquid chromatography
- the compound can exist predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) .
- the presence and/or amounts of stereoisomers can be determined by those skilled in the art in view of the present disclosure, including through the use of a chiral HPLC or SFC or other methods.
- C 1–6 is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , 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 .
- the term “compound (s) of the present disclosure” refers to any of the compounds described herein according to Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos.
- Formula I e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1,
- I-IX isotopically labeled compound (s) thereof (such as a deuterated analog wherein one or more of the hydrogen atoms is/are substituted with a deuterium atom with an abundance above its natural abundance, e.g., a CD 3 analog when the compound has a CH 3 group) , possible regioisomers, possible geometric isomers, possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures, such as Formula I-EN2 or Formula II-EN2) , tautomers thereof, conformational isomers thereof, pharmaceutically acceptable esters thereof, and/or possible pharmaceutically acceptable salts thereof (e.g., acid addition salt such as HCl salt or base addition salt such as Na salt) .
- acid addition salt such as HCl salt or base addition salt such as Na salt
- compositions of the present disclosure wherein the compound (s) is in association with water or solvent, respectively.
- Compound Nos. I-IX should be understood as a compound having a structure according to those labeled as I, II, ..., IX in the Examples section herein.
- Isotopes can be radioactive or non-radioactive isotopes.
- Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl, and 125 I.
- Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
- administering means providing the compound or a prodrug of the compound to the individual in need of treatment.
- alkyl refers to a straight-or branched-chain aliphatic saturated hydrocarbon.
- the alkyl can include one to twelve carbon atoms (i.e., C 1-12 alkyl) or the number of carbon atoms designated.
- the alkyl group is a straight chain C 1-10 alkyl group.
- the alkyl group is a branched chain C 3-10 alkyl group.
- the alkyl group is a straight chain C 1-6 alkyl group.
- the alkyl group is a branched chain C 3-6 alkyl group.
- the alkyl group is a straight chain C 1-4 alkyl group.
- a C 1-4 alkyl group includes methyl, ethyl, propyl (n-propyl) , isopropyl, butyl (n-butyl) , sec-butyl, tert-butyl, and iso-butyl.
- the term "alkylene" as used by itself or as part of another group refers to a divalent radical derived from an alkyl group.
- non-limiting straight chain alkylene groups include -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -, and the like.
- alkenyl refers to a straight-or branched-chain aliphatic hydrocarbon containing one or more, for example, one, two or three carbon-to-carbon double bonds.
- the alkenyl group is a C 2-6 alkenyl group.
- the alkenyl group is a C 2-4 alkenyl group.
- Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
- alkynyl refers to a straight-or branched-chain aliphatic hydrocarbon containing one or more, for example, one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C 2-6 alkynyl group. In another embodiment, the alkynyl group is a C 2-4 alkynyl group.
- Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
- alkoxy as used by itself or as part of another group refers to a radical of the formula OR a1 , wherein R a1 is an alkyl.
- cycloalkoxy as used by itself or as part of another group refers to a radical of the formula OR a1 , wherein R a1 is a cycloalkyl.
- haloalkyl refers to an alkyl substituted with one or more fluorine, chlorine, bromine and/or iodine atoms.
- the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms.
- the haloalkyl group is a C 1-10 haloalkyl group.
- the haloalkyl group is a C 1-6 haloalkyl group.
- the haloalkyl group is a C 1-4 haloalkyl group.
- heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched-chain alkyl group, e.g., having from 2 to 14 carbons, such as 2 to 10 carbons in the chain, one or more of the carbons has been replaced by a heteroatom selected from S, O , P and N, and wherein the nitrogen, phosphine, and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized.
- the heteroatom (s) S, O , P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
- the substituent (s) can replace one or more hydrogen atoms attached to the carbon atom (s) and/or the heteroatom (s) of the heteroalkyl.
- the heteroalkyl is a C 1-4 heteroalkyl, which refers to the heteroalkyl defined herein having 1-4 carbon atoms.
- C 1-4 heteroalkyl examples include, but are not limited to, C 4 heteroalkyl such as -CH 2 -CH 2 -N (CH 3 ) -CH 3 , C 3 heteroalkyl such as -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 - NH-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 -S (O) -CH 3 , -CH 2 -CH 2 -S (O) 2 -CH 3 , C 2 heteroalkyl such as -CH 2 -CH 2 -OH, -CH 2 -CH 2 -NH 2 , -CH 2 -NH (CH 3 ) , -O-CH 2 -CH 3 and C 1 heteroalkyl such as, -CH 2 -OH, -CH 2 -NH 2 , -O-CH 3 .
- C 4 heteroalkyl such as -CH 2 -
- heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -O-CH 2 -CH 2 -and –O-CH 2 -CH 2 -NH-CH 2 -.
- heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like) .
- no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
- heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R” or the like, it will be understood that the terms heteroalkyl and -NR'R” are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
- Carbocyclyl or “carbocyclic” as used by itself or as part of another group refers to a radical of a non–aromatic cyclic hydrocarbon group having at least 3 carbon atoms, e.g., from 3 to 10 ring carbon atoms ( “C 3–10 carbocyclyl” ) , and zero heteroatoms in the non–aromatic ring system.
- the carbocyclyl group can be either monocyclic ( “monocyclic carbocyclyl” ) or contain a fused, bridged or spiro ring system such as a bicyclic system ( “bicyclic carbocyclyl” ) and can be saturated or can be partially unsaturated.
- the carbocyclyl groups herein also include ring systems in which one or more rings are aryl ring (s) , provided that the carbocyclyl ring as a whole is not aromatic, and the point of attachment can be on any ring.
- Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.
- the term "carbocyclylene” as used by itself or as part of another group refers to a divalent radical derived from the carbocyclyl group defined herein.
- “carbocyclyl” is fully saturated, which is also referred to as cycloalkyl.
- the cycloalkyl can have from 3 to 10 ring carbon atoms ( “C 3–10 cycloalkyl” ) .
- the cycloalkyl is a monocyclic ring.
- the term "cycloalkylene" as used by itself or as part of another group refers to a divalent radical derived from a cycloalkyl group, for example, etc.
- Heterocyclyl or “heterocyclic” as used by itself or as part of another group refers to a radical of a 3-membered or larger, such as 3–to 14–membered, non–aromatic ring system having ring carbon atoms and at least one ring heteroatom, such as 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon.
- the point of attachment can be a carbon or nitrogen atom, as valency permits.
- a heterocyclyl group can either be monocyclic ( “monocyclic heterocyclyl” ) or a fused, bridged, or spiro ring system, such as a bicyclic system ( “bicyclic heterocyclyl” ) , and can be saturated or can be partially unsaturated.
- Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings, and the point of attachment can be on any ring.
- the heterocyclyl groups herein also include ring systems in which one or more rings are aryl or heteroaryl ring (s) , provided that the heterocyclyl ring as a whole is not a heteroaryl ring, and the point of attachment can be on any ring.
- heterocyclylene as used by itself or as part of another group refers to a divalent radical derived from the heterocyclyl group defined herein.
- the heterocyclyl or heterocylylene can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.
- heterocyclyl groups include azirdinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl–2, 5–dione, dioxolanyl, oxasulfuranyl, disulfuranyl, oxazolidin-2-one, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinanyl, azepanyl, oxepanyl, thiophenyl
- Aryl as used by itself or as part of another group refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ( “C 6–14 aryl” ) .
- an aryl group has six ring carbon atoms ( “C 6 aryl” ; e.g., phenyl) .
- an aryl group has ten ring carbon atoms ( “C 10 aryl” ; e.g., naphthyl such as 1–naphthyl and 2–naphthyl) .
- an aryl group has fourteen ring carbon atoms ( “C 14 aryl” ; e.g., anthracyl) .
- the term "arylene” as used by itself or as part of another group refers to a divalent radical derived from the aryl group defined herein.
- Alkyl as used by itself or as part of another group refers to an alkyl substituted with one or more aryl groups, preferably, substituted with one aryl group. Examples of aralkyl include benzyl, phenethyl, etc. When an aralkyl is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl can be optionally substituted.
- Heteroaryl as used by itself or as part of another group refers to a radical of a 5–14 membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and at least one, preferably, 1–4, ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ( “5–14 membered heteroaryl” ) .
- the heteroaryl described herein can be a 5-10 membered heteroaryl, for example, a 5-or 6-membered heteroaryl, or 8-10 membered bicyclic heteroaryl.
- the point of attachment can be a carbon or nitrogen atom, as valency permits.
- Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
- heteroarylene as used by itself or as part of another group refers to a divalent radical derived from the heteroaryl group defined herein.
- heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, puriny
- Heteroaralkyl as used by itself or as part of another group refers to an alkyl substituted with one or more heteroaryl groups, preferably, substituted with one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.
- an “optionally substituted” group such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refers to the respective group that is unsubstituted or substituted.
- substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
- a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position.
- the optionally substituted groups herein can be substituted with 1-5 substituents.
- Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable.
- Two of the optional substituents can join to form a ring structure, such as an optionally substituted cycloalkyl, heterocylyl, aryl, or heteroaryl ring. Substitution can occur on any available carbon, oxygen, or nitrogen atom, and can form a spirocycle.
- substitution herein does not result in an O-O, O-N, S-S, S-N (except SO 2 -N bond) , heteroatom-halogen, or -C (O) -Sbond or three or more consecutive heteroatoms, with the exception of O-SO 2 -O, O-SO 2 -N, and N-SO 2 -N, except that some of such bonds or connections may be allowed if in a stable aromatic system.
- the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
- the permissible substituents can be one or more and the same or different for appropriate organic compounds.
- the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
- Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl) , a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , an alkoxy, a cycloalkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aral
- substituents include, but not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C (O) -aryl, halo, -NO 2 , -CN, -SF 5 , -C (O) OH, -C (O) O-alkyl, -C (O) O-aryl, -C (O) O-alkylene-aryl, -S (O) -alkyl, -S (O
- substituents include, but not limited to, (C 1 -C 8 ) alkyl groups, (C 2 -C 8 ) alkenyl groups, (C 2 -C 8 ) alkynyl groups, (C 3 -C 10 ) cycloalkyl groups, halogen (F, Cl, Br or I) , halogenated (C 1 -C 8 ) alkyl groups (for example but not limited to -CF 3 ) , -O- (C 1 -C 8 ) alkyl groups, -OH, -S- (C 1 -C 8 ) alkyl groups, -SH, -NH (C 1 -C 8 ) alkyl groups, -N ( (C 1 -C 8 ) alkyl) 2 groups, -NH 2 , -C (O) NH 2 , -C (O) NH (C 1 -C 8 ) alkyl groups, -C (O) N ( (C 1 -C 8
- Exemplary carbon atom substituents include, but are not limited to, halogen, –CN, –NO 2 , –N 3 , hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkyl amino, dialkyl amino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3–10 carbocyclyl, C 6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl, etc.
- Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
- Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfone, sulfoxide, C 1–10 alkyl, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclyl, 3–14 membered heterocyclyl, C 6–14 aryl, and 5–14 membered heteroaryl, or two substituent groups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein.
- the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group) .
- Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated by reference herein.
- Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl.
- carbamates such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert
- oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, C 1–10 alkyl, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclyl, 3–14 membered heterocyclyl, C 6–14 aryl, and 5–14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein.
- the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group) .
- Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
- oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM) , benzyloxymethyl (BOM) , 2–methoxyethoxymethyl (MEM) , etc., those forming silyl ethers, such as trymethylsilyl (TMS) , triethylsilyl (TES) , triisopropylsilyl (TIPS) , t-butyldimethylsilyl (TBDMS) , etc., those forming acetals or ketals, such as tetrahydropyranyl (THP) , those forming esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc.,
- a “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject) .
- the “optionally substituted” alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocyclic, carbocyclylene, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclyl, or heterocyclylene herein can each be independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, -OH, protected hydroxyl, oxo (as applicable) , NH 2 , protected amino, NH (C 1-4 alkyl) or a protected derivative thereof, N (C 1-4 alkyl ( (C 1-4 alkyl) , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2, or 3 ring
- Halo or “halogen” refers to fluorine (fluoro, –F) , chlorine (chloro, –Cl) , bromine (bromo, –Br) , or iodine (iodo, –I) .
- pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art.
- tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from tautomerization. The exact ratio of the tautomers depends on several factors, including for example temperature, solvent, and pH. Tautomerizations are known to those skilled in the art. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to- (adifferent enamine) tautomerizations.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- the terms “treat, “ “treating, “ “treatment, “ and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
- the terms “treat, “ “treating, “ “treatment, “ and the like may include “prophylactic treatment, “ which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
- the term “treat” and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.
- an effective amount refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, prophylaxis or treatment of diseases.
- a therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo) , or the subject and disease condition being treated (e.g., the weight, age and gender of the subject) , the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art.
- the term also applies to a dose that will induce a particular response in target cells and/or tissues. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.
- Headings and subheadings are used for convenience and/or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology.
- Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.
- the mixture was quenched with saturated solution of sodium bicarbonate (15 mL) at -30 °C, followed by hydrogen peroxide (30%aqueous solution, 7 mL) at -10 °C, and the resulting mixture was stirred at 10 °C for additional 1 hr.
- the aqueous layer was extracted with ethyl acetate (20 mL x 3) , and the combined organic layers were washed with saturated solution of sodium sulfite (20 mL) and brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- the reaction mixture was diluted with ethyl acetate (150 mL x 3) .
- the organic layer was washed with brine (50 mL x 3) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- the residue was subjected to silica gel column chromatography to afford N-methoxy-N-methyl-3-oxocyclopentane-1-carboxamide (22, 13.1 g, 97%) as a yellow solid.
- reaction mixture was quenched with saturated solution of ammonium chloride (120 mL) at 0 °C and extracted with ethyl acetate (120 mL x 3) .
- the combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- the residue was subjected to silica gel column chromatography to afford dimethyl 4-bromo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3, 5-dicarboxylate (II-3, 18.8 g, 89%yield from 2) as a colorless oil.
- the reaction mixture was degassed and backfilled with nitrogen three times, and stirred at 110 °C under N 2 atmosphere for 5 hrs.
- the reaction mixture was cooled to room temperature and filtered.
- the filtrate was diluted with ethyl acetate (200 mL) , washed with brine (80 mL x 2) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- the residue was subjected to silica gel column chromatography to afford dimethyl 4-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3, 5-dicarboxylate (II-4, 3.48 g, 83%) as a yellow oil.
- N- (2, 6-dichloropyridin-4-yl) nitramide (IV-2, 11.2 g, 53.8 mmol) was added to concentrated sulfuric acid (100 ml) in portions at -40 °C. The mixture was heated to 100 °C and stirred for 1 hr. The reaction mixture was poured into ice water (1 L) , adjusted to pH 9-10 with 6 M aq. NaOH and stirred at room temperature for additional 30 mins. A precipitation was formed and the solid was collected by filtration. The filter cake was dried in vacuum to afford 2, 6-dichloro-3-nitropyridin-4-amine (IV-3, 8.50 g, 76%) as a white solid.
- reaction mixture was quenched with water (15 mL) and extracted with dichloromethane (15 mL x 3) .
- the combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- reaction mixture was quenched with saturated aq. NH 4 Cl (20 mL) at 0 °C and extracted with ethyl acetate (20 mL x 3) .
- the combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3) .
- the combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- the mixture was warmed to room temperature and stirred for 2 hrs.
- the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3) .
- the combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL x 3) .
- the combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- Analytical method Column: ChiralPak AD, 150 ⁇ 4.6 mm I.D., 3 ⁇ m; Mobile phase: A for CO 2 and B for Isopropanol (0.05%DEA) ; Gradient: B 25%; Flow rate: 2.4 mL/min; Back pressure: 100 bar; Column temperature: 35 °C; Wavelength: 220 nm.
- SFC Method Instrument: MG II preparative SFC (SFC-1) ; Column: ChiralPak AD, 250 ⁇ 30 mm I.D., 10 ⁇ m; Mobile phase: A for CO 2 and B for Isopropanol (0.1%NH 3 ⁇ H 2 O) ; Gradient: B 20%; Flow rate: 60 mL /min; Back pressure: 100 bar; Column temperature: 38°C; Wavelength: 220 nm; Cycle time: ⁇ 4 mins.
- reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (15 mL x 3) .
- the combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3) .
- the combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3) .
- the combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue.
- Compounds of the present disclosure are expected to be CDK2 inhibitors.
- the IC50 values of compounds of the present disclosure against various CDKs can be measured by using the experimental procedures described below, which have been used for testing other CDK2 inhibitors.
- CDK2/CyclinE1 kinase inhibitory activity (IC50) : 5 ⁇ l of various dilutions of test compound in 1x kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Brij-35) was mixed with 10 ⁇ L of CDK2/CyclinE1 (Carna, 04-165#, final concentration 3 nM in 1 ⁇ Kinase buffer) in 384 plates and incubated at room temperature for 10 min.
- 1x kinase buffer 50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Brij-35
- Caliper EZ reader II Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide 18 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II.
- %Inhibition [ (MA –X) / (MA -MI) ] ⁇ 100%
- MA conversion value of DMSO only controls
- MI conversion value of no enzyme controls
- X conversion value at any given compound dose.
- IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
- CDK1/CyclinB kinase inhibitory activity (IC50) : 5 ⁇ l of various dilutions of test compound in 1x kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Brij-35) was mixed with 10 ⁇ L of CDK1/CyclinB (Millipore, 14-450M#, final concentration 3 nM in 1 ⁇ Kinase buffer) in 384 plates and incubated at room temperature for 10 min.
- 1x kinase buffer 50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Brij-35
- Caliper EZ reader II Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide 18 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II.
- %Inhibition [ (MA –X) / (MA -MI) ] ⁇ 100%
- MA conversion value of DMSO only controls
- MI conversion value of no enzyme controls
- X conversion value at any given compound dose.
- IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
- CDK4/CyclinD1 or CDK4/CyclinD3 kinase inhibitory activity 5 ⁇ l of various dilutions of test compound in 1x kinase buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Triton X-100 ) was mixed with 10 ⁇ L of either CDK4/Cyclin D1 (ProQinase, 0142-0143-1#, final concentration 20nM in 1 x Kinase buffer) or CDK4/CyclinD3 (Carna, 04-105#, final concentration 10nM in 1 ⁇ Kinase buffer) in 384 plates and incubated at room temperature for 10 min.
- 1x kinase buffer 20 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Triton X-100
- reaction is then allowed to proceed at 28°C for 30min and terminated by the addition of 25 ⁇ L stop buffer (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2%Coating Reagent #3 (Perkin Elmer, 760050#) and 0.015%Brij-35) .
- stop buffer 100 mM HEPES pH 7.5, 50 mM EDTA, 0.2%Coating Reagent #3 (Perkin Elmer, 760050#) and 0.015%Brij-35
- Caliper EZ reader II Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide 8 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II.
- %Inhibition [ (MA –X) / (MA -MI) ] ⁇ 100%
- MA conversion value of DMSO only controls
- MI conversion value of no enzyme controls
- X conversion value at any given compound dose.
- IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
- CDK6/CyclinD1 or CDK6/CyclinD3 kinase inhibitory activity IC50: 5 ⁇ l of various dilutions of test compound in 1x kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Brij-35) was mixed with 10 ⁇ L of CDK6/CyclinD1 (Carna, 04-114#, final concentration 7.5nM in 1 ⁇ Kinase buffer) or CDK6/Cyclin D3 (Carna, 04-107#, final concentration 15nM in 1 ⁇ Kinase buffer) in 384 plates and incubated at room temperature for 10 min.
- 1x kinase buffer 50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Brij-35
- reaction is then allowed to proceed at 28°C for 30min and terminated by the addition of 25 ⁇ L stop buffer (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2%Coating Reagent #3 (Perkin Elmer, 760050#) and 0.015%Brij-35) .
- stop buffer 100 mM HEPES pH 7.5, 50 mM EDTA, 0.2%Coating Reagent #3 (Perkin Elmer, 760050#) and 0.015%Brij-35
- Caliper EZ reader II Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide 8 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II.
- %Inhibition [ (MA –X) / (MA -MI) ] ⁇ 100%
- MA conversion value of DMSO only controls
- MI conversion value of no enzyme controls
- X conversion value at any given compound dose.
- IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
- CDK7/CyclinH/MAT1 kinase inhibitory activity (IC50) : 5 ⁇ l of various dilutions of test compound in 1x kinase buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Triton X-100) was mixed with 10 ⁇ L of CDK7/CyclinH/MAT1 (Millipore, 14-476M#, final concentration 12.5nM in 1 ⁇ Kinase buffer) in 384 plates and incubated at room temperature for 10 min.
- 1x kinase buffer 20 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Triton X-100
- Caliper EZ reader II Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide CTD3 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II.
- %Inhibition [ (MA –X) / (MA -MI) ] ⁇ 100%
- MA conversion value of DMSO only controls
- MI conversion value of no enzyme controls
- X conversion value at any given compound dose.
- IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
- CDK9/CyclinT1 kinase inhibitory activity (IC50) : 5 ⁇ l of various dilutions of test compound in 1x kinase buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Triton X-100) was mixed with 10 ⁇ L of CDK9/CyclinT1 (Millipore, 14-685M#, final concentration 12.5nM in 1 ⁇ Kinase buffer) in 384 plates and incubated at room temperature for 10 min.
- 1x kinase buffer 20 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Triton X-100
- Caliper EZ reader II Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide CTD3 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II.
- %Inhibition [ (MA –X) / (MA -MI) ] ⁇ 100%
- MA conversion value of DMSO only controls
- MI conversion value of no enzyme controls
- X conversion value at any given compound dose.
- IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
- Biological activity data for representative compounds of the present disclosure are provided in Table 2 below. Exemplary results are presented as calculated IC 50 values.
- A represents a calculated IC 50 value of less than 10 nM
- B represents a calculated IC 50 value of greater than or equal to 10 nM and less than 100 nM
- C represents a calculated IC 50 value of greater than or equal to 100 nM and less than 1 ⁇ M
- D represents a calculated IC 50 value of 1 ⁇ M or greater.
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Abstract
Provided herein are novel compounds (e.g., Formula I or II), pharmaceutical compositions, and methods of using related to cyclin dependent kinases (CDKs). The compounds herein are typically CDK2 inhibitors, which can be used for treating a variety of diseases or disorders, such as cancer.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority of International Application No. PCT/CN2020/138390, filed December 22, 2020, the content of which is incorporated herein by reference in its entirety for all purposes.
In various embodiments, the present disclosure generally relates to novel cyclopentane compounds, compositions comprising the same, methods of preparing and methods of using the same, e.g., for inhibiting cyclin-dependent kinases and/or for treating or preventing various diseases or disorders described herein.
Cyclin-dependent kinase (CDKs) are a family of serine/threonine protein kinases that regulate the cell cycle progression. Among CDKs, CDK2 is an essential driver for cells to transition from late G1 into S and G2 phases. During late G1, CDK2 is activated upon binding to cyclin E. The cyclin E/CDK2 complex hyper-phosphorylates RB to release E2F from Rb and initiate transcription of genes necessary for G1/Stransition. Subsequently, CDK2 forms complex with Cyclin A to regulate S phase progression by activating proteins important for DNA replication and centrosome duplication, such as DNA replication licensing 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) .
Cyclin E1 is frequently amplified and/or overexpressed in human cancer. In high grade serous ovarian cancer, cyclin E1 amplification is detected in approximately 20%of patients and is associated with chemo 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) . Cyclin E1 amplified ovarian cancer cell lines are sensitive to reagents that either inhibit CDK2 activity or decrease cellular CDK2 protein level, suggesting CDK2 dependence in these cyclin E1 amplified cells (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) . Poor outcomes and drug resistance were also associated with high Cyclin E1 expression in endometrial, gastric, breast and other cancers (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, Hum Pathol. (2017) 61: 58-67; Keyomarsi et al., Cyclin E and survival in patients with breast cancer. N Engl J Med. (2002) 347: 1566-75) . Estrogen receptor (ER) positive breast cancer cell lines with acquired resistance to CDK4/6 inhibitor Palbociclib has elevated cyclin E1 expression and can be re-sensitized upon knock down of CDK2 (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) . High cyclin E1 level was also reported to associate with poor response to Palbociclib plus fulvestrant combo therapy in ER+BC (CCNE1 high vs CCNE1 low: median PFS for Palbociclib+fulvestrant arm, 7.6 v 14.1 month; placebo+fulvestrant arm, 4.0 v 4.8 month) further underline 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) .
Cyclin E2 (CCNE2) overexpression was reported as associated with endocrine resistance in breast cancer cells and CDK2 inhibition has been reported to restore sensitivity to tamoxifen or 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) . Additionally, Cyclin E amplification has also been reported as contributing 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) . Further, Cyclin E overexpression was 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. )
BRIEF SUMMARY
The importance of CDK2 in proliferative pathways and the frequently altered CDK2/cyclin E1 activity in tumor highlights CDK2 as a target for cancer treatment. CDK2 knock out mice are viable with minimum defects, suggesting CDK2 is not essential for normal cell proliferation (Berthet et al., CDK2 knock out mice are viable. Curr Biol. (2003) 13 (20) : 1775-85) . In addition, selective CDK2 inhibitors may minimize clinical toxicity while being active in treating patients with high tumor cyclinE1 and/or E2 expression. However, in some embodiments, inhibiting CDK2 as well as other CDKs can also be clinically beneficial.
In various embodiments, the present disclosure relates to novel cyclopentane compounds which can inhibit CDK2, e.g., selectively over other CDKs and/or other kinases. The compounds and compositions herein are useful for treating various diseases or disorders, such as cancer, e.g., those characterized with amplification or overexpression of Cyclin E1 (CCNE1) and/or cyclin E2 (CCNE2) .
Some embodiments of the present disclosure are directed to a compound of Formula I or II, or a pharmaceutically acceptable salt thereof,
wherein the variables are defined herein. In some embodiments, the compound of Formula I can have a sub-formula of I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c as defined herein. In some embodiments, the compound of Formula II can have a subformula of II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b, as defined herein. In some embodiments, the present disclosure also provides specific compounds selected from the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof.
In some embodiments, the present disclosure provides a pharmaceutical composition comprising one or more compounds of the present disclosure and optionally a pharmaceutically acceptable excipient. The pharmaceutical composition can be typically formulated for oral administration.
In some embodiments, the present disclosure also provides a method of inhibiting CDK activity such as CDK2 activity in a subject or biological sample. In some embodiments, the method comprises contacting the subject or biological sample with an effective amount of one or more compounds of the present disclosure, e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
In some embodiments, the present disclosure provides a method of treating or preventing a CDK-mediated disease or disorder in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of one or more compounds of the present disclosure or the pharmaceutical composition herein. In some embodiments, the method comprises administering to the subject an effective amount of a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
In some embodiments, the present disclosure also provides a method of treating or preventing cancer in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I- C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a 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 (i.e., gastric) cancer, thyroid cancer, and combinations thereof. In some embodiments, the cancer is breast cancer selected from ER-positive/HR-positive, HER2-negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC) ; and inflammatory breast cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is breast cancer selected from endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating 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.
The administering in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In some embodiments, the administering is orally. In some embodiments, the administering is a parenteral injection, such as an intraveneous injection.
Compounds of the present disclosure can be used as a monotherapy or in a combination therapy. In some embodiments according to the methods described herein, one or more compounds of the present disclosure can be administered as the only active ingredient (s) . In some embodiments, the method herein further comprises administering to the subject an additional therapeutic agent, such as additional anticancer agents described herein.
It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention herein.
In various embodiments, the present disclosure provides compounds and compositions that are useful for inhibiting CDKs such as CDK2 and/or treating or preventing various diseases or disorders described herein, e.g., cancer.
Compounds
The compounds herein can typically inhibit CDK2. In some embodiments, the compounds herein can selectively inhibit CDK2 over other CDKs, for example, over CDK1, with a selectivity of more than 10-fold, and up to about 30-fold and beyond.
Formula I
In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
L
1 is a bond, NH, O, optionally substituted C
1-4 alkylene, optionally substituted C
1-4 heteroalkylene, or
R
1 is an optionally substituted 5-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl (e.g., 5-or 6-membered heteroaryl, or 8-10 membered bicyclic heteroaryl) ;
X is NR
10 or O;
Y is a bond, O, NR
10, optionally substituted C
1-4 alkylene, or optionally substituted C
1-4 heteroalkylene;
R
2 is hydrogen, an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or NR
11R
12;
wherein:
R
10 at each occurrence is independently hydrogen, an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl;
each of R
11 and R
12 is independently hydrogen, an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl; or a nitrogen protecting group; or R
11 and R
12, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl.
The compound of Formula I (including any of the applicable sub-formulae as described herein) comprises at least two asymmetric centers. Typically, with respect to the two asymmetric centers shown in Formula I, the compound of Formula I exists predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) . In some embodiments, the compound of Formula I can also exist in a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
While the as-drawn stereoisomer of the compound of Formula I is preferred for the purposes herein, in some embodiments, the other enantiomer of the as-drawn stereoisomer of the compound of Formula I (including any of the applicable sub-formulae as described herein) is also provided, which can exist in a substantially pure form or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. For example, in some embodiments, the other enantiomer, Formula I-EN2, can exist as an individual enantiomer substantially free (e.g., with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount) of the as-drawn enantiomer of the compound of Formula I:
wherein the definitions of variables for Formula I-EN2 can be the same as those defined herein for Formula I.
In some embodiments, L
1 in Formula I is a bond, which means that R
1 is directly linked to the pyrazole ring, and Formula I can be represented by Formula I-A:
wherein R
1, R
2, X, and Y include any of those described herein in any combination.
In some embodiments, L
1 in Formula I is NH, and Formula I can be represented by Formula I-B:
wherein R
1, R
2, X, and Y include any of those described herein in any combination.
In embodiments according to Formula I-A (e.g., I-A-1, I-A-2, or I-A-3) , R
1 is typically an optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S. For example, in some embodiments, R
1 is an optionally substituted imidazole.
In some specific embodiments, the compound of Formula I can be characterized as having Formula I-1:
wherein:
R
20 and R
21 are each independently OH, halogen, CN, R
g1, OR
g1, C (O) R
g1, C (O) OR
g1, S (O) R
g1, S (O)
2R
g1, S (O)
2NR
aR
b, C (O) NR
aR
b, NR
aR
b or S (O) (NR
c) R
g1; or R
20 and R
21, together with the intervening atoms, form an optionally substituted 4-8 membered ring, e.g., an optionally substituted phenyl or optionally substituted 5-or 6-membered heteroaryl;
wherein:
R
a and R
b are each independently R
g1, C (O) R
g1, C (O) OR
g1, or C (O) NR
g1R
g1, or a nitrogen protecting group; or R
a and R
b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;
R
c is hydrogen or C
1-4 alkyl; and
R
g1 at each occurrence is independently hydrogen, an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl, and
R
2, X, and Y include any of those described herein in any combination.
In some embodiments, in Formula I-1 (e.g., I-1-a, I-1-b, or I-1-c) , R
20 and R
21 are each independently hydrogen, OH, halogen, CN, R
g2, C (O) R
g2, or S (O)
2R
g2,
wherein R
g2 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, phenyl, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, or 5-or 6-membered heteroaryl is independently optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , oxo (as valency permits) , OH, CN, C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R
s2,
wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and
R
s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C
1-4 alkoxy optionally substituted with 1-3 F.
In some embodiments, in Formula I-1 (e.g., I-1-a, I-1-b, or I-1-c) , R
20 and R
21 are each independently hydrogen, halogen, CN, C
1-4 alkyl, C (O) -C
1-4 alkyl, S (O)
2-C
1-4 alkyl, C
1-4 alkyl substituted with 1-3 fluorine, C
1-4 heteroalkyl, C
1-4 heteroalkyl substituted with 1-3 fluorine, phenyl, pyridyl, or pyrazolyl, wherein the phenyl, pyridyl, or pyrazolyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R
s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C
1-4 alkoxy optionally substituted with 1-3 F.
In some embodiments, in Formula I-1 (e.g., I-1-a, I-1-b, or I-1-c) , R
20 and R
21 are each independently hydrogen, C
1-4 alkyl, C (O) -C
1-4 alkyl, S (O)
2-C
1-4 alkyl, C
1-4 alkyl substituted with 1-3 fluorine, C
1-4 heteroalkyl, C
1-4 heteroalkyl substituted with 1-3 fluorine, or a group selected from the following:
In any of the embodiments described herein, unless otherwise specified or contrary from context, in Formula I-1 (e.g., I-1-a, I-1-b, or I-1-c) , one of R
20 and R
21 can be hydrogen, for example, R
20 is hydrogen or R
21 is hydrogen.
In some embodiments, in Formula I-1 (e.g., I-1-a, I-1-b, or I-1-c) , R
20 and R
21, together with the intervening atoms, can also form an optionally substituted phenyl or an optionally substituted 5-or 6-membered heteroaryl.
For example, in some embodiments, in Formula I-1 (e.g., I-1-a, I-1-b, or I-1-c) , R
20 and R
21, together with the intervening atoms, can form a phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
g2, C (O) R
g2, or S (O)
2R
g2,
wherein R
g2 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, phenyl, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, or 5-or 6-membered heteroaryl is independently optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , oxo (as valency permits) , OH, CN, C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R
s2,
wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and
R
s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C
1-4 alkoxy optionally substituted with 1-3 F.
In some embodiments, in Formula I-1 (e.g., I-1-a, I-1-b, or I-1-c) , R
20 and R
21, together with the intervening atoms, can form a phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one or more (e.g., 1, or 2) substituents each independently halogen (e.g., F or Cl) , CN, OH, C (O) -C
1-4 alkyl, S (O)
2-C
1-4 alkyl, C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R
s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C
1-4 alkoxy optionally substituted with 1-3 F. In some embodiments, in Formula I-1 (e.g., I-1-a, I-1-b, or I-1-c) , R
20 and R
21, together with the intervening atoms, can form a phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one or more (e.g., 1, or 2) substituents each independently selected from F, Cl, methyl, ethyl, CH
3OCH
2, methoxy, CH
3S (O)
2CH
2, CH
3CO, oxetanyl, CH
3CF
2, and isopropyl.
In any of the embodiments described herein, unless otherwise specified or contrary from context, in Formula I-1 (e.g., I-1-a, I-1-b, or I-1-c) , the
moiety can be selected from the following:
In any of the embodiments described herein, unless otherwise specified or contrary from context, in Formula I-1 (e.g., I-1-a, I-1-b, or I-1-c) , the
moiety can be
In some embodiments, the compound of Formula I can be characterized as having Formula I-B as described herein.
In embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R
1 can be an optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S. For example, in some embodiments, R
1 is an optionally substituted 6-membered heteroaryl, such as pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
For example, in some embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R
1 can be pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
h1, OR
h1, C (O) R
h1, C (O) H, C (O) OR
h1, COOH, S (O) R
h1, S (O)
2R
h1, S (O)
2NR
aR
b, C (O) NR
aR
b, NR
aR
b or S (O) (NR
c) R
h1,
wherein R
a and R
b are each independently hydrogen, R
h1, C (O) H, C (O) R
h1, C (O) OR
h1, CONH
2, C (O) NHR
h1, or C (O) NR
h1R
h1, or a nitrogen protecting group; or R
a and R
b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;
R
c is hydrogen or C
1-4 alkyl; and
wherein R
h1 at each occurrence is independently an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R
1 can be pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
h2 or OR
h2,
wherein R
h2 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R
s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C
1-4 alkoxy optionally substituted with 1-3 F.
In some embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R
1 can be selected from:
wherein the pyridyl, pyridazinyl, or pyrazinyl is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R
h3 or OR
h3, wherein R
h3 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, or C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl. In some embodiments, the pyridyl, pyridazinyl, or pyrazinyl is substituted with one or two substituents each independently methyl, F, Cl, CN,
In some embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R
1 can be a 5, 6-bicyclic or 6, 6-bicyclic heteroaryl having 1-4 ring heteroatoms independently selected from N, O, and S, which can be optionally substituted. In some embodiments, the 5, 6-bicyclic or 6, 6-bicyclic heteroaryl can be optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
h1, OR
h1, C (O) R
h1, C (O) H, C (O) OR
h1, COOH, S (O) R
h1, S (O)
2R
h1, S (O)
2NR
aR
b, C (O) NR
aR
b, NR
aR
b or S (O) (NR
c) R
h1,
wherein R
a and R
b are each independently hydrogen, R
h1, C (O) H, C (O) R
h1, C (O) OR
h1, CONH
2, C (O) NHR
h1, or C (O) NR
h1R
h1, or a nitrogen protecting group; or R
a and R
b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;
R
c is hydrogen or C
1-4 alkyl; and
wherein R
h1 at each occurrence is independently an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
In some specific embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R
1 can be selected from:
each of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R
h2 or OR
h2, wherein R
h2 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more substituents (e.g., 1, 2, or 3) each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R
s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C
1-4 alkoxy optionally substituted with 1-3 F.
In some specific embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R
1 can be selected from:
each of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R
h3 or OR
h3, wherein R
h3 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, and C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl. In some embodiments, the foregoing bicyclic heteroaryl is substituted with one or two substituents each independently methyl, methyl substituted with 1-3 F (e.g., CF
3) , F, Cl, CN,
In some embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R
1 can be selected from:
In some preferred embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R
1 can be
In some preferred embodiments according to Formula I-B (e.g., I-B-1, I-B-2, or I-B-3) , R
1 can be
In some embodiments according to Formula I-B, R
1 can be
wherein R
110 is halogen (e.g., F or Cl) or optionally substituted C
1-3 alkyl, such as those substituted with 1-3 fluorine, such as CF
3.
wherein R
1, R
2, X, and Y include any of those described herein in any combination. For example, R
1 for Formula I-C can include any of those described herein above in connection with Formula I-A or I-B.
In some embodiments, L
1 in Formula I can also be an optionally substituted C
1-4 alkylene.
In some embodiments, L
1 in Formula I can also be an optionally substituted C
1-4 heteroalkylene.
Typically, in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , X is O.
In some embodiments, in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , X can be NR
10, wherein R
10 is defined herein. For example, in some embodiments, X can be NH.
Typically, in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , Y is NH.
In some embodiments, in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , Y can be a bond, in which case, R
2 is bonded directly with the carbonyl group. In some embodiments, in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , Y can be O. In some embodiments, in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , Y can also be an optionally substituted C
1-4 alkylene, such as CH
2. In some embodiments, in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) , Y can also be an optionally substituted C
1-4 heteroalkylene.
The combination of X and Y is not particularly limited. In any of the embodiments described herein, unless otherwise specified or contrary from context, in Formula I (e.g., Formula I-A, I-B, I-C, or I-1) ,
in Formula I can be
For example, in some embodiments, the compound of Formula I, such as I-A, I-B, I-C, or I-1, can be characterized as having a structure according to the following subformulae I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-1-a, I-1-b, I-1-c, I-C-1, I-C-2, or I-C-3:
wherein the variables R
1, R
2, R
20, and R
21 can be any of those defined herein in connection with Formula I, including any applicable subformulae, in any combinations.
In Formula I, various groups are suitable as R
2. For example, in some embodiments, R
2 can be hydrogen. In some embodiments, R
2 can be an optionally substituted C
1-6 alkyl. In some embodiments, R
2 can be an optionally substituted C
3-8 carbocyclyl. In some embodiments, R
2 can be an optionally substituted 4-10 membered heterocyclyl. In some embodiments, R
2 can be an optionally substituted phenyl. In some embodiments, R
2 can be an optionally substituted 5-10 membered heteroaryl. In some embodiments, R
2 can be NR
11R
12, wherein R
11 and R
12 are defined herein.
In some embodiments, in Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) , R
2 can be a C
1-6 alkyl, such as isopropyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, oxo (as valency permits) , C
1-4 heteroalkyl optionally substituted with 1-3 F, C
3-6 cycloalkyl, or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, wherein the C
3-6 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with halogen (e.g., F or Cl) , OH, CN, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, or C
1-4 heteroalkyl optionally substituted with 1-3 F.
In some embodiments, in Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) , R
2 can be a C
3-6 cycloalkyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, or C
1-4 heteroalkyl optionally substituted with 1-3 F.
In some embodiments, in Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) , R
2 can be a 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , R
s3, OR
s3, or C (O) R
s3, wherein R
s3 at each occurrence is independently C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s4, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s4, C
3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s4, or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted with one or more (e.g., 1, 2, or 3) R
s4, wherein R
s4 at each occurrence is independently F, OH, CN, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, or C
1-4 heteroalkyl optionally substituted with 1-3 F.
In any of the embodiments described herein, unless specified or otherwise contrary from context, in Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) , R
2 can be selected from:
As would be apparent to those skilled in the art, some of the specific structures for R
2 as shown above has one or more asymmetric centers. The present disclosure is not limited to any particular stereoisomer. In some embodiments, the compound of Formula I having such R
2 groups can also be enriched in one or more of the stereoisomers. For example, in some embodiments, the compound of Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) can exist predominantly as a stereoisomer with R
2 selected from the following groups with the configuration (s) as drawn below:
For example, in some embodiments, in Formula I, with respect to R
2 groups, the compound can exist predominantly as the as-drawn stereoisomer shown above, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) . However, in some embodiments, with respect to R
2 groups, the compound of Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) can also exist in a mixture of stereoisomers in any molar ratio, including 1: 1 ratio of a pair of enantiomers of the applicable R
2 groups.
In any of the embodiments described herein, unless specified or otherwise contrary from context, in Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) , R
2 can be isopropyl or cyclopropyl.
In any of the embodiments described herein, unless specified or otherwise contrary from context, in Formula I (e.g., Formula I-A, I-B, I-C, I-D, I-A-1, I-B-1, I-C-1, I-1, or I-1-a) ,
can be
Formula II
In some embodiments, the present disclosure provides a compound of Formula II, or a pharmaceutically acceptable salt thereof:
wherein:
A is an optionally substituted 5-membered or 6-membered heteroaryl, optionally substituted 8-10 membered bicyclic heteroaryl,
L
2 is a bond, O, optionally substituted C
1-4 alkylene, optionally substituted C
1-4 heteroalkylene, NH,
R
3 is L
3- (phenyl) , L
3- (5-10 membered heterocyclyl) or L
3- (5-10 membered heteroaryl) , wherein the phenyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl (e.g., 5-or 6-membered heteroaryl, or 8-10 membered bicyclic heteroaryl) is optionally substituted, and L
3 is a bond, an optionally substituted C
1-4 alkylene, or optionally substituted C
1-4 heteroalkylene;
X is NR
10 or O;
Y is a bond, O, NR
10, optionally substituted C
1-4 alkylene, or optionally substituted C
1-4 heteroalkylene;
R
2 is hydrogen, an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or NR
11R
12;
wherein:
R
10 at each occurrence is independently hydrogen, an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl;
each of R
11 and R
12 is independently hydrogen, an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl; or a nitrogen protecting group; or R
11 and R
12, together with the nitrogen atom they are attached, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl.
The compound of Formula II (including any of the applicable sub-formulae as described herein) comprises at least two asymmetric centers. Typically, with respect to the two asymmetric centers shown in Formula II, the compound of Formula II exists predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) . In some embodiments, the compound of Formula II can also exist in a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
While the as-drawn stereoisomer of the compound of Formula II is preferred for the purposes herein, in some embodiments, the other enantiomer of the as-drawn stereoisomer of the compound of Formula II (including any of the applicable sub-formulae as described herein) is also provided, which can exist in a substantially pure form or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. For example, in some embodiments, the other enantiomer Formula II-EN2, can exist as an individual enantiomer substantially free (e.g., with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount) of the as-drawn enantiomer of the compound of Formula II:
wherein the definitions of variables for Formula II-EN2 can be the same as those defined herein for Formula II.
Various heteroaryls are suitable as A in Formula II. In some embodiments, A in Formula II can be an optionally substituted 5-membered heteroaryl, such as an optionally substituted imidazole. For example, in some embodiments, the compound of Formula II can be characterized as having a Formula II-A:
wherein L
2, R
3, R
2, X, and Y include any of those described herein in any combination.
In some typical embodiments, L
2 in Formula II-A is NH or
and the compound of Formula II-A can be characterized as having a Formula II-A-1 or II-A-2:
wherein R
3, R
2, X, and Y include any of those described herein in any combination.
In some embodiments, L
2 in Formula II-A can also be a bond. In some embodiments, L
2 in Formula II-A can also be O. In some embodiments, L
2 in Formula II-A can also be an optionally substituted C
1-4 alkylene, such as CH
2. In some embodiments, L
2 in Formula II-A can also be an optionally substituted C
1-4 heteroalkylene. In some embodiments, L
2 in Formula II-A can also be
In some typical embodiments of Formula II where L
2 is NH, such as in Formula II-A-1, R
3 can be L
3- (5-10 membered heteroaryl) , wherein the 5-10 membered heteroaryl is optionally substituted. Typically, in such embodiments, L
3 is a bond. However, in some embodiments, L
3 can be an optionally substituted C
1-4 alkylene. In some embodiments, L
3 can be an optionally substituted C
1-4 heteroalkylene.
In some embodiments of Formula II where L
2 is NH, such as in Formula II-A-1, R
3 can be an optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, such as pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl.
For example, in some embodiments of Formula II where L
2 is NH, such as in Formula II-A-1, R
3 can be pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R
h1, OR
h1, C (O) R
h1, C (O) H, C (O) OR
h1, COOH, S (O) R
h1, S (O)
2R
h1, S (O)
2NR
aR
b, C (O) NR
aR
b, NR
aR
b or S (O) (NR
c) R
h1, wherein R
a and R
b are each independently hydrogen, R
h1, C (O) H, C (O) R
h1, C (O) OR
h1, CONH
2, C (O) NHR
h1, or C (O) NR
h1R
h1, or a nitrogen protecting group; or R
a and R
b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;
R
c is hydrogen or C
1-4 alkyl; and
R
h1 at each occurrence is independently an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments of Formula II where L
2 is NH, such as in Formula II-A-1, R
3 can be pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R
h2 or OR
h2,
wherein R
h2 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R
s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C
1-4 alkoxy optionally substituted with 1-3 F.
In some embodiments of Formula II where L
2 is NH, such as in Formula II-A-1, R
3 can be selected from:
wherein the pyridyl, pyridazinyl, or pyrazinyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
h3 or OR
h3, wherein R
h3 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl. In some embodiments, the pyridyl, pyridazinyl, or pyrazinyl is substituted with one or two substituents each independently methyl, F, Cl, CN,
In some embodiments of Formula II where L
2 is NH, such as in Formula II-A-1, R
3 can be an optionally substituted 5, 6-bicyclic or 6, 6-bicyclic heteroaryl having 1-4 ring heteroatoms independently selected from N, O, and S. For example, in some embodiments, the 5, 6-bicyclic or 6, 6-bicyclic heteroaryl can be optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
h1, OR
h1, C (O) R
h1, C (O) H, C (O) OR
h1, COOH, S (O) R
h1, S (O)
2R
h1, S (O)
2NR
aR
b, C (O) NR
aR
b, NR
aR
b or S (O) (NR
c) R
h1, wherein R
a and R
b are each independently hydrogen, R
h1, C (O) H, C (O) R
h1, C (O) OR
h1, CONH
2, C (O) NHR
h1, or C (O) NR
h1R
h1, or a nitrogen protecting group; or R
a and R
b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;
R
c is hydrogen or C
1-4 alkyl; and
R
h1 at each occurrence is independently an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments of Formula II where L
2 is NH, such as in Formula II-A-1, R
3 can be selected from:
each of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1 or 2) substituents each independently OH, halogen, CN, R
h2 or OR
h2,
wherein R
h2 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R
s2, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R
s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C
1-4 alkoxy optionally substituted with 1-3 F.
In some embodiments of Formula II where L
2 is NH, such as in Formula II-A-1, R
3 can be selected from:
each of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
h3 or OR
h3,
wherein R
h3 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, and C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
In some embodiments of Formula II where L
2 is NH, such as in Formula II-A-1, R
3 can be selected from:
each of the foregoing bicyclic heteroaryls is substituted with one or two substituents each independently methyl, F, Cl, CN,
In some embodiments of Formula II where L
2 is NH, such as in Formula II-A-1, R
3 can be selected from:
In some typical embodiments of Formula II where L
2 is
such as in Formula II-A-2, R
3 can be L
3- (phenyl) or L
3- (5-10 membered heteroaryl) , wherein the phenyl or 5-10 membered heteroaryl is optionally substituted. In some embodiments, L
3 is a bond. In some embodiments, L
3 is an optionally substituted C
1-4 alkylene. In some embodiments, L
3 is an optionally substituted C
1-4 heteroalkylene.
In some embodiments of Formula II where L
2 is
such as in Formula II-A-2, R
3 can be -CH
2-R
30 or R
30, wherein R
30 is an optionally substituted phenyl or optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S. For example, in some embodiments, the compound of Formula II-A-2 can be characterized as having Formula II-A-2a or II-A-2b:
wherein R
30, R
2, X, and Y include any of those described herein in any combination.
For example, in some embodiments of Formula II where R
3 is -CH
2-R
30 or R
30, such as in Formula II-A-2a or II-A-2b, R
30 can be selected from:
each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
h2, S (O)
2R
h2 or OR
h2,
wherein R
h2 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
In some embodiments of Formula II where R
3 is -CH
2-R
30 or R
30, such as in Formula II-A-2a or II-A-2b, R
30 can be selected from:
each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
h2, S (O)
2R
h2 or OR
h2,
wherein R
h2 at each occurrence is independently a C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,
wherein the C
1-4 alkyl, C
3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s1, wherein R
s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
In some embodiments, R
30 can be selected from:
each of which can be substituted with one or two substituents each independently methyl, F, Cl, methyl, ethyl, CH
3OCH
2, methoxy, CH
3S (O)
2, CH
3S (O)
2CH
2, CH
3CO, oxetanyl, tetrahydrofuranyl, CH
3CF
2, and isopropyl.
In any of the embodiments described herein, unless otherwise specified or contrary from context, L
2-R
3 in Formula II-A-2 can be selected from:
In some embodiments, A in Formula II can be an optionally substituted 6-membered heteroaryl having 1-3 ring nitrogen atoms, such as an optionally substituted pyrazine or optionally substituted triazine. For example, in some embodiments, the compound of Formula II can be characterized as having a Formula II-B or II-C:
wherein the pyrazine or triazine is optionally substituted with a substituent selected from F, Cl, CN, OH, methyl, methoxy, or OCD
3, and
L
2, R
3, R
2, X, and Y include any of those described herein in any combination.
In embodiments according to Formula II where A is 6-membered heteroaryl, such as Formula II-B or II-C, L
2 is typically NH.
In embodiments according to Formula II where A is 6-membered heteroaryl, such as Formula II-B or II-C, R
3 is typically an optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-10 membered heterocycles.
For example, in some embodiments of Formula II where A is 6-membered heteroaryl, such as in Formula II-B or II-C, R
3 can be selected from:
each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
h1, OR
h1, C (O) R
h1, C (O) H, C (O) OR
h1, COOH, S (O) R
h1, S (O)
2R
h1, S (O)
2NR
aR
b, C (O) NR
aR
b, NR
aR
b or S (O) (NR
c) R
h1, provided that at least one of the substituents is S (O) (NR
c) R
h1, S (O)
2R
h1, S (O)
2NR
aR
b or C (O) NR
aR
b, wherein R
a and R
b are each independently hydrogen, R
h1, C (O) H, C (O) R
h1, C (O) OR
h1, CONH
2, C (O) NHR
h1, or C (O) NR
h1R
h1, or a nitrogen protecting group; or R
a and R
b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;
R
c is hydrogen or C
1-4 alkyl; and
R
h1 at each occurrence is independently an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
In some more specific embodiments of Formula II where A is 6-membered heteroaryl, such as in Formula II-B or II-C, R
3 can be selected from:
wherein
R
j is OH, halogen, CN, C
1-4 alkyl, C
1-4 alkoxy, or C
3-6 cycloalkyl, and
R
h2 is C
1-4 alkyl or C
3-6 cycloalkyl,
wherein each of the C
1-4 alkyl, C
1-4 alkoxy, or C
3-6 cycloalkyl is optionally substituted with 1-3 F,
wherein R
a, R
b, and R
c are defined herein in connection with R
3 in Formula II-B or II-C. Typically, the NR
aR
b is NH
2.
In any of the embodiments described herein, unless otherwise specified or contrary from context, in Formula II where A is 6-membered heteroaryl, such as Formula II-B or II-C, R
3 can be selected from:
In some embodiments, A in Formula II can also be an optionally substituted 8-10 membered bicyclic heteroaryl, such as an optionally substituted 5, 6-bicyclic heteroaryl having 1-4 ring nitrogen atoms. Typically, in such embodiments, the ring that immediately connected to the cyclopentane ring in Formula II is an imidazole or pyrazole ring, whereas the ring distal to the cyclopentane ring is typically a pyridine, pyrimidine, pyridazine, pyrazine, or triazine ring.
For example, in some embodiments, A in Formula II can be selected from:
each of which is optionally substituted with a substituent selected from F, Cl, CN, OH, methyl, methoxy, or OCD
3.
For example, in some embodiments, the compound of Formula II can be characterized as having a formula II-D:
wherein n is 0 or 1, and when n is 1, R
100 is F, Cl, CN, OH, methyl, methoxy, or OCD
3 and
L
2, R
3, R
2, X, and Y include any of those described herein in any combination. It should be understood that when n is 1, R
100 may be attached at either the 5-member ring or the 6-member ring of the bicyclic heteroaryl, although preferably, the attach point is on the 6-membered ring.
In some embodiments, the compound of Formula II can be characterized as having a formula II-E:
wherein n is 0 or 1, and when n is 1, R
100 is F, Cl, CN, OH, methyl, methoxy, or OCD
3 and
L
2, R
3, R
2, X, and Y include any of those described herein in any combination. It should be understood that when n is 1, R
100 may be attached at either the 5-member ring or the 6-member ring of the bicyclic heteroaryl, although preferably, the attach point is on the 6-membered ring.
In some embodiments, the compound of Formula II can be characterized as having a formula II-F:
wherein n is 0 or 1, and when n is 1, R
100 is F, Cl, CN, OH, methyl, methoxy, or OCD
3 and
L
2, R
3, R
2, X, and Y include any of those described herein in any combination. It should be understood that when n is 1, R
100 may be attached at either the 5-member ring or the 6- member ring of the bicyclic heteroaryl, although preferably, the attach point is on the 6-membered ring.
In some embodiments, the compound of Formula II can be characterized as having a formula II-G:
wherein n is 0 or 1, and when n is 1, R
100 is F, Cl, CN, OH, methyl, methoxy, or OCD
3 and
L
2, R
3, R
2, X, and Y include any of those described herein in any combination. It should be understood that when n is 1, R
100 may be attached at either the 5-member ring or the 6-member ring of the bicyclic heteroaryl, although preferably, the attach point is on the 6-membered ring.
In some embodiments, the compound of Formula II can be characterized as having a formula II-H:
wherein n is 0 or 1, and when n is 1, R
100 is F, Cl, CN, OH, methyl, methoxy, or OCD
3 and
L
2, R
3, R
2, X, and Y include any of those described herein in any combination. It should be understood that when n is 1, R
100 may be attached at either the 5-member ring or the 6-member ring of the bicyclic heteroaryl, although preferably, the attach point is on the 6-membered ring.
In embodiments where A is a bicyclic heteroaryl, such as Formula II-D to II-H, L
2 is typically NH.
In embodiments where A is a bicyclic heteroaryl, such as Formula II-D to II-H, R
3 can typically be represented by the formula: C (R
40) (R
41) -R
42, wherein:
R
40 and R
41 are independently hydrogen, deuterium, or methyl, or R
40 and R
41, together with the carbon they are both attached to, form an optionally substituted C
3-6 cycloalkyl or optionally substituted 4-8 membered heterocyclyl, and
R
42 is an optionally substituted phenyl or optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S. In some embodiments, R
40 and R
41 are the same, and both are hydrogen, deuterium, or methyl. In some embodiments, R
40 is hydrogen, and R
41 is deuterium or methyl. In some embodiments, R
40 and R
41, together with the carbon they are both attached to, form a cyclopropyl.
Various phenyl or heteroaryl groups are suitable R
42 groups. In some embodiments, when R
3 is C (R
40) (R
41) -R
42, R
40 and R
41 are defined herein, R
42 can be selected from:
each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R
h1, OR
h1, C (O) R
h1, C (O) H, C (O) OR
h1, COOH, S (O) R
h1, S (O)
2R
h1, S (O)
2NR
aR
b, C (O) NR
aR
b, NR
aR
b or S (O) (NR
c) R
h1, wherein R
a and R
b are each independently hydrogen, R
h1, C (O) H, C (O) R
h1, C (O) OR
h1, CONH
2, C (O) NHR
h1, or C (O) NR
h1R
h1, or a nitrogen protecting group; or R
a and R
b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;
R
c is hydrogen or C
1-4 alkyl; and
R
h1 at each occurrence is independently an optionally substituted C
1-6 alkyl, optionally substituted C
3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, when R
3 is C (R
40) (R
41) -R
42, R
40 and R
41 are defined herein, R
42 can be selected from:
each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, C
1-4 alkyl, or C
1-4 alkoxy, wherein the C
1-4 alkyl or C
1-4 alkoxy is optionally substituted with 1-3 F.
In some embodiments, when R
3 is C (R
40) (R
41) -R
42, R
40 and R
41 are defined herein, R
42 can be selected from:
each of which is substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CH
3OCH
2, methyl, ethyl, or methoxy.
In any of the embodiments according to Formula II where A is a bicyclic heteroaryl, such as Formula II-D to II-H, unless otherwise specified or contrary from context, R
3 can be selected from:
Typically, in Formula II (e.g., any of the subformulae, such as II-A to II-H) , X can be O or NH.
Typically, in Formula II (e.g., any of the subformulae, such as II-A to II-H) , Y can be O, NH, a bond or CH
2.
For example, in any of the embodiments according to Formula II, such as Formula II-A to II-H, unless otherwise specified or contrary from context,
in Formula II can be
In any of the embodiments according to Formula II, such as Formula II-A to II-H, unless otherwise specified or contrary from context,
in Formula II can be
In Formula II, various groups are suitable as R
2. For example, in some embodiments, R
2 can be hydrogen. In some embodiments, R
2 can be an optionally substituted C
1-6 alkyl. In some embodiments, R
2 can be an optionally substituted C
3-8 carbocyclyl. In some embodiments, R
2 can be an optionally substituted 4-10 membered heterocyclyl. In some embodiments, R
2 can be an optionally substituted phenyl. In some embodiments, R
2 can be an optionally substituted 5-10 membered heteroaryl. In some embodiments, R
2 can be NR
11R
12, wherein R
11 and R
12 are defined herein.
In some embodiments, in Formula II (e.g., Formula II-A to II-H) , R
2 can be a C
1-6 alkyl, such as isopropyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, oxo (as valency permits) , C
1-4 heteroalkyl optionally substituted with 1-3 F, C
3-6 cycloalkyl, or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, wherein the C
3-6 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with halogen (e.g., F or Cl) , OH, CN, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, or C
1-4 heteroalkyl optionally substituted with 1-3 F.
In some embodiments, in Formula II (e.g., Formula II-A to II-H) , R
2 can be a C
3-6 cycloalkyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, or C
1-4 heteroalkyl optionally substituted with 1-3 F.
In some embodiments, in Formula II (e.g., Formula II-A to II-H) , R
2 can be a 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , R
s3, OR
s3, or C (O) R
s3, wherein R
s3 at each occurrence is independently C
1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s4, C
1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s4, C
3-
6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R
s4, or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted with one or more (e.g., 1, 2, or 3) R
s4, wherein R
s4 at each occurrence is independently F, OH, CN, oxo (as valency permits) , C
1-4 alkyl optionally substituted with 1-3 F, or C
1-4 heteroalkyl optionally substituted with 1-3 F.
In any of the embodiments described herein, unless specified or otherwise contrary from context, in Formula II (e.g., Formula II-A to II-H) , R
2 can be selected from:
As would be apparent to those skilled in the art, some of the specific structures for R
2 as shown above has one or more asymmetric centers. The present disclosure is not limited to any particular stereoisomer. However, in some embodiments, the compound of Formula II having such R
2 groups can also be enriched in one or more of the stereoisomers. For example, in some embodiments, the compound of Formula II (e.g., Formula II-A to II-H) can exist predominantly as a stereoisomer with R
2 selected from the following groups with the configuration (s) as drawn below:
For example, in some embodiments, in Formula II, with respect to R
2 groups, the compound can exist predominantly as the as-drawn stereoisomer shown above, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) . However, in some embodiments, with respect to R
2 groups, the compound of Formula II (e.g., Formula II-A to II-H) can also exist in a mixture of stereoisomers in any molar ratio, including 1: 1 ratio of a pair of enantiomers of the applicable R
2 groups.
In some embodiments, the present disclosure also provide a compound selected from Table 1A below, or a pharmaceutically acceptable salt thereof:
Table 1A. List of Exemplary Compounds
In some embodiments, the present disclosure also provide a compound selected from Table 1B below, or a pharmaceutically acceptable salt thereof:
Table 1B. List of Exemplary Compounds
Compounds of Table 1A and 1B can exist in various stereoisomeric forms, such as individual isomer, an individual enantiomer and/or diastereomer, as applicable, or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, when applicable, a compound shown Table 1A or 1B can exist as the as-drawn enantiomer substantially free (e.g., with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount) of the other enantiomer. In some embodiments, when applicable, a compound shown Table 1A or 1B can also exist as a mixture of stereoisomers in any ratio, such as a racemic mixture.
In some embodiments, the present disclosure also provide a compound selected from the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof.
In some embodiments, to the extent applicable, the genus of compounds described herein also excludes any specifically known single compounds prior to this disclosure. In some embodiments, to the extent applicable, any sub-genus or species of compounds prior to this disclosure that are entirely within a genus of compounds described herein can also be excluded from such genus herein.
The compounds of the present disclosure can be readily synthesized by those skilled in the art in view of the present disclosure. Similar synthetic processes can also be found in WO2020/157652, the content of which is herein incorporated by reference in its entirety. The reagents for preparing the compounds herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of such reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) , Sigma (St. Louis, Missouri, USA) . Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991) , Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989) , Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991) , March's Advanced Organic Chemistry, (Wiley, 7
th Edition) , and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999) , and any of available updates as of this filing.
Pharmaceutical Compositions
Certain embodiments are directed to a pharmaceutical composition comprising one or more compounds of the present disclosure.
The pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference) , which discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
The pharmaceutical composition can include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition comprises a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof, e.g., in a therapeutically effective amount. Unless specified or otherwise contrary, in any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effective amount (e.g., for treating breast cancer or ovarian cancer) of a compound selected from the specific compounds disclosed in Table 1A herein, or a pharmaceutically acceptable salt thereof. Unless specified or otherwise contrary, in any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effective amount (e.g., for treating breast cancer or ovarian cancer) of a compound selected from the specific compounds disclosed in Table 1B herein, or a pharmaceutically acceptable salt thereof. Unless specified or otherwise contrary, in any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effective amount (e.g., for treating breast cancer or ovarian cancer) of a compound selected from the compounds according to Compound Nos. I-IX herein, for example, Compound No. I, II, or III, or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition herein can be formulated for delivery via any of the known routes of delivery, which include but not limited to administering orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally or parenterally.
In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non- aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for the preparation of compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1, 3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.
In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection) . The parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1, 3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.
Compounds of the present disclosure can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, e.g., in combination with an additional anticancer therapeutic agent, such as mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like. In some embodiments, one or more compounds of the present disclosure can be used in combination with one or more targeted agents, such as inhibitors of PI3 kinase, mTOR, PARP, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, Src/Abl, RTK/Ras, Myc, Raf, PDGF, AKT, c-Kit, erbB, CDK4/CDK6, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1, EZH2 or Hsp90, or immunomodulatory agents, such as PD-1 or PD-L1 antagonists, OX40 agonists or 4-1BB agonists. In some embodiments, one or more compounds of the present disclosure can be used in combination with a standard of care agent, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole or trastuzumab. Suitable additional anticancer therapeutic agent include any of those known in the art, such as those approved for the appropriate cancer by a regulatory agency such as the U.S. Food and Drug Administration. Some examples of suitable additional anticancer therapeutic agents also include those described in WO2020/157652, US2018/0044344, WO2008/122767, etc., the content of each of which is herein incorporated by reference in its entireties.
When used in combination with one or more additional therapeutic agents, compounds of the present disclosure or pharmaceutical compositions herein can be administered to the subject either concurrently or sequentially in any order with such additional therapeutic agents. In some embodiments, the pharmaceutical composition can comprise one or more compounds of the present disclosure and the one or more additional therapeutic agents in a single composition. In some embodiments, the pharmaceutical composition comprising one or more compounds of the present disclosure can be included in a kit which also comprises a separate pharmaceutical composition comprising the one or more additional therapeutic agents.
The pharmaceutical composition can include various amounts of the compounds of the present disclosure, depending on various factors such as the intended use and potency and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, such as breast cancer or ovarian cancer, which can depend on the recipient of the treatment, the disorder, condition or disease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.
Method of Treatment/Use
Compounds of the present disclosure have various utilities. For example, compounds of the present disclosure can be used as therapeutic active substances for the treatment and/or prophylaxis of a CDK2-mediated disease or disorder. Accordingly, some embodiments of the present disclosure are also directed to methods of using one or more compounds of the present disclosure or pharmaceutical compositions herein for treating or preventing a CDK2-mediated disease or disorder in a subject in need thereof, such as for treating cancer in a subject in need thereof.
In some embodiments, the present disclosure provides a method of inhibiting abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition described herein. In some embodiments, the abnormal cell growth is cancer characterized by amplification or overexpression of cyclin E1 (CCNE1) and/or cyclin E2 (CCNE2) . In some embodiments, the subject is identified as having a cancer characterized by amplification or overexpression of CCNE1 and/or CCNE2.
In some embodiments, the present disclosure also provides a method of inhibiting CDK activity in a subject or biological sample. In some embodiments, the present disclosure provides a method of inhibiting CDK2 activity in a subject or biological sample, which comprises contacting the subject or biological sample with an effective amount of the compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein.
In some embodiments, the present disclosure provides a method of treating or preventing a CDK mediated, in particular CDK2-mediated disease or disorder in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the CDK2-mediated disease or disorder is cancer. In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2
In some embodiments, the present disclosure also provides a method of treating or preventing cancer in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a 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 a 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, stomach (i.e., 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 stomach cancer.
In some embodiments of the methods herein, the cancer is breast cancer, such as ER-positive/HR-positive, HER2-negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC) ; or inflammatory breast cancer. In some embodiments, the breast cancer can be endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer can 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.
In some embodiments of the methods herein, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
In some embodiments of the methods herein, the cancer is blood cancer such as leukemia. In some embodiments of the methods herein, the cancer is chronic lymphocytic leukemia, such as relapsed or refractory Chronic Lymphocytic Leukemia (CLL) .
In some embodiments of the methods herein, the cancer is acute myeloid leukemia. In some embodiments of the methods herein, the cancer is relapsed or refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes.
In any of the embodiments described herein, unless otherwise specified or contradictory, the cancer herein can be characterized by amplification or overexpression of CCNE1 and/or CCNE2.
In some embodiments, the present disclosure also provides a method of treating breast cancer in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the breast cancer is selected from ER-positive/HR-positive, HER2-negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC) ; and inflammatory breast cancer. In some embodiments, the breast cancer is selected from endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating 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.
In some embodiments, the present disclosure also provides a method of treating ovarian cancer in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the ovarian cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
In some embodiments, the present disclosure also provides a method of treating leukemia in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the leukemia is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
In some embodiments, the present disclosure also provides a method of treating chronic lymphocytic leukemia, such as relapsed or refractory Chronic Lymphocytic Leukemia (CLL) , in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein.
In some embodiments, the present disclosure also provides a method of treating acute myeloid leukemia, such as relapsed or refractory Acute Myeloid Leukemia, in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein.
In some embodiments, the present disclosure also provides a method of treating Myelodysplastic Syndromes in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein.
The administering in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In some embodiments, the administering is orally. In some embodiments, the administering is a parenteral injection, such as an intraveneous injection.
Compounds of the present disclosure can be used as a monotherapy or in a combination therapy. In some embodiments according to the methods described herein, one or more compounds of the present disclosure can be administered as the only active ingredient (s) . In some embodiments according to the methods described herein, one or more compounds of the present disclosure can also be co-administered with an additional therapeutic agent, either concurrently or sequentially in any order, to the subject in need thereof. The additional therapeutic agent can typically be an additional anticancer therapeutic agent, such as mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like. In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor, a SERD or a SERM. In some embodiments, one or more compounds of the present disclosure can be administered in combination with one or more 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 immunomodulatory agents, such as PD-1 or PD-L1 antagonists, OX40 agonists or 4-1BB agonists. In some embodiments, one or more compounds of the present disclosure can be administered administered in combination with a standard of care agent, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole or trastuzumab. Suitable additional anticancer therapeutic agent include any of those known in the art, such as those approved for the appropriate cancer by a regulatory agency such as the U.S. Food and Drug Administration. Some examples of suitable additional anticancer therapeutic agents also include those described in WO2020/157652, US2018/0044344, WO2008/122767, etc., the contents of each of which is incorporated by reference herein in their entirety.
Dosing regimen including doses for the methods described herein can vary and be adjusted, which can depend on the recipient of the treatment, the disorder, condition or disease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.
Definitions
It is meant to be understood that proper valences are maintained for all moieties and combinations thereof.
It is also meant to be understood that a specific embodiment of a variable moiety herein can be the same or different as another specific embodiment having the same identifier.
Suitable groups for the variables in compounds of Formula I, or a subformula thereof, as applicable, are independently selected. Non-limiting useful groups for the variables in compounds of Formula I, or a subformula thereof, as applicable, include any of the respective groups, individually or in any combination, as shown in the specific compounds described in Table 1A or 1B herein. Using variable R
1 as an example, in some embodiments, compounds of Formula I can include a R
1 group according to any of the R
1 groups shown in the specific compounds described in Table 1A or 1B herein, without regard to the other variables shown in the specific compounds. In some embodiments, compounds of Formula I can include a R
1 group according to any of the R
1 groups shown in the specific compounds described in Table 1A or 1B herein in combination at least one other variable (e.g, L
1) according to the specific compounds described in Table 1A or 1B herein, wherein the R
1 and at least one other variable can derive from the same compound or a different compound. Any of such combinations are contemplated and within the scope of the present disclosure.
The described embodiments of the present disclosure can be combined. Such combination is contemplated and within the scope of the present disclosure. For example, it is contemplated that the definition (s) of any one or more of L
1, R
1, R
2, X, and Y of Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) can be combined with the definition of any one or more of the other (s) of L
1, R
1, R
2, X, and Y, as applicable, and the resulted compounds from the combination are within the scope of the present disclosure. Similar combinations of variables are also contemplated in connection with Formula II.
The symbol,
displayed perpendicular to (or otherwise crossing) a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule. It should be noted that the immediately connected group or groups or variable (s) maybe shown beyond the symbol,
to indicate connectivity, as would be understood by those skilled in the art.
Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75
th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5
th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3
rd Edition, Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents described herein.
Compounds described herein can comprise one or more asymmetric centers in addition to those shown in Formula I or II, and can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Wilen et al., Tetrahedron 33: 2725 (1977) ; Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962) ; and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972) . The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers including racemic mixtures. When a stereochemistry is specifically drawn, unless otherwise contradictory from context, it should be understood that with respect to that particular chiral center or axial chirality, the compound can exist predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) . The presence and/or amounts of stereoisomers can be determined by those skilled in the art in view of the present disclosure, including through the use of a chiral HPLC or SFC or other methods. As used herein, when a "*" is shown in the chemical structures herein, unless otherwise contradictory from context, it is to designate that the corresponding chiral center is enantiomerically pure or enriched in either of the configurations or is enantiomerically pure or enriched in the as-dawn configuration, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC or SFC area, or both, or with a non-detectable amount of the other stereoisomer (s) . Also, when no stereochemistry is specifically drawn, and no "*" is used in the chemical structures, unless otherwise contradictory from context, it should be understood that such structures include the corresponding compound in any stereoisomeric forms, including individual isomers substantially free of other isomers and mixtures of various isomers including racemic mixtures.
When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example “C
1–6” is intended to encompass, C
1, C
2, C
3, C
4, C
5, C
6, 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.
As used herein, the term “compound (s) of the present disclosure” refers to any of the compounds described herein according to Formula I (e.g., I-A, I-B, I-C, I-D, I-A-1, I-A-2, I-A-3, I-B-1, I-B-2, I-B-3, I-C-1, I-C-2, I-C-3, I-1, I-1-a, I-1-b, or I-1-c) , Formula II (e.g., II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-A-1, II-A-2, II-A-2a, or II-A-2b) , or any of the specific compounds disclosed in Table 1A or 1B herein, any of the compounds according to Compound Nos. I-IX herein, isotopically labeled compound (s) thereof (such as a deuterated analog wherein one or more of the hydrogen atoms is/are substituted with a deuterium atom with an abundance above its natural abundance, e.g., a CD
3 analog when the compound has a CH
3 group) , possible regioisomers, possible geometric isomers, possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures, such as Formula I-EN2 or Formula II-EN2) , tautomers thereof, conformational isomers thereof, pharmaceutically acceptable esters thereof, and/or possible pharmaceutically acceptable salts thereof (e.g., acid addition salt such as HCl salt or base addition salt such as Na salt) . Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, wherein the compound (s) is in association with water or solvent, respectively. Compound Nos. I-IX should be understood as a compound having a structure according to those labeled as I, II, …, IX in the Examples section herein.
Compounds of the present disclosure can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to
2H,
3H,
13C,
14C,
15N,
18O,
32P,
35S,
18F,
36Cl, and
125I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
As used herein, the phrase “administration” of a compound, “administering” a compound, or other variants thereof means providing the compound or a prodrug of the compound to the individual in need of treatment.
As used herein, the term "alkyl" as used by itself or as part of another group refers to a straight-or branched-chain aliphatic saturated hydrocarbon. In some embodiments, the alkyl can include one to twelve carbon atoms (i.e., C
1-12 alkyl) or the number of carbon atoms designated. In one embodiment, the alkyl group is a straight chain C
1-10 alkyl group. In another embodiment, the alkyl group is a branched chain C
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 chain C
3-6 alkyl group. In another embodiment, the alkyl group is a straight chain C
1-4 alkyl group. For example, a C
1-4 alkyl group includes methyl, ethyl, propyl (n-propyl) , isopropyl, butyl (n-butyl) , sec-butyl, tert-butyl, and iso-butyl. As used herein, the term "alkylene" as used by itself or as part of another group refers to a divalent radical derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH
2-CH
2-CH
2-CH
2-, -CH
2-CH
2-CH
2-, -CH
2-CH
2-, and the like.
As used herein, the term "alkenyl" as used by itself or as part of another group refers to a straight-or branched-chain aliphatic hydrocarbon containing one or more, for example, one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C
2-6 alkenyl group. In another embodiment, the alkenyl group is a C
2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
As used herein, the term "alkynyl" as used by itself or as part of another group refers to a straight-or branched-chain aliphatic hydrocarbon containing one or more, for example, one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C
2-6 alkynyl group. In another embodiment, the alkynyl group is a C
2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
As used herein, the term "alkoxy" as used by itself or as part of another group refers to a radical of the formula OR
a1, wherein R
a1 is an alkyl.
As used herein, the term "cycloalkoxy" as used by itself or as part of another group refers to a radical of the formula OR
a1, wherein R
a1 is a cycloalkyl.
As used herein, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl substituted with one or more fluorine, chlorine, bromine and/or iodine atoms. In preferred embodiments, the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is a C
1-10 haloalkyl group. In one embodiment, the haloalkyl group is a C
1-6 haloalkyl group. In one embodiment, the haloalkyl group is a C
1-4 haloalkyl group.
As used herein, the term "heteroalkyl, " by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched-chain alkyl group, e.g., having from 2 to 14 carbons, such as 2 to 10 carbons in the chain, one or more of the carbons has been replaced by a heteroatom selected from S, O
, P and N, and wherein the nitrogen, phosphine, and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom (s) S, O
, P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When the heteroalkyl is said to be substituted, the substituent (s) can replace one or more hydrogen atoms attached to the carbon atom (s) and/or the heteroatom (s) of the heteroalkyl. In some embodiments, the heteroalkyl is a C
1-4 heteroalkyl, which refers to the heteroalkyl defined herein having 1-4 carbon atoms. Examples of C
1-4 heteroalkyl include, but are not limited to, C
4 heteroalkyl such as -CH
2-CH
2-N (CH
3) -CH
3, C
3 heteroalkyl such as -CH
2-CH
2-O-CH
3, -CH
2-CH
2- NH-CH
3, -CH
2-S-CH
2-CH
3, -CH
2-CH
2-S (O) -CH
3, -CH
2-CH
2-S (O)
2-CH
3, C
2 heteroalkyl such as -CH
2-CH
2-OH, -CH
2-CH
2-NH
2, -CH
2-NH (CH
3) , -O-CH
2-CH
3 and C
1 heteroalkyl such as, -CH
2-OH, -CH
2-NH
2, -O-CH
3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH
2-CH
2-O-CH
2-CH
2-and –O-CH
2-CH
2-NH-CH
2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R” or the like, it will be understood that the terms heteroalkyl and -NR'R” are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
“Carbocyclyl” or “carbocyclic” as used by itself or as part of another group refers to a radical of a non–aromatic cyclic hydrocarbon group having at least 3 carbon atoms, e.g., from 3 to 10 ring carbon atoms ( “C
3–10 carbocyclyl” ) , and zero heteroatoms in the non–aromatic ring system. The carbocyclyl group can be either monocyclic ( “monocyclic carbocyclyl” ) or contain a fused, bridged or spiro ring system such as a bicyclic system ( “bicyclic carbocyclyl” ) and can be saturated or can be partially unsaturated. For the avoidance of doubt, the carbocyclyl groups herein also include ring systems in which one or more rings are aryl ring (s) , provided that the carbocyclyl ring as a whole is not aromatic, and the point of attachment can be on any ring. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term "carbocyclylene" as used by itself or as part of another group refers to a divalent radical derived from the carbocyclyl group defined herein.
In some embodiments, “carbocyclyl” is fully saturated, which is also referred to as cycloalkyl. In some embodiments, the cycloalkyl can have from 3 to 10 ring carbon atoms ( “C
3–10 cycloalkyl” ) . In preferred embodiments, the cycloalkyl is a monocyclic ring. As used herein, the term "cycloalkylene" as used by itself or as part of another group refers to a divalent radical derived from a cycloalkyl group, for example,
etc.
“Heterocyclyl” or “heterocyclic” as used by itself or as part of another group refers to a radical of a 3-membered or larger, such as 3–to 14–membered, non–aromatic ring system having ring carbon atoms and at least one ring heteroatom, such as 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ( “monocyclic heterocyclyl” ) or a fused, bridged, or spiro ring system, such as a bicyclic system ( “bicyclic heterocyclyl” ) , and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings, and the point of attachment can be on any ring. For the avoidance of doubt, the heterocyclyl groups herein also include ring systems in which one or more rings are aryl or heteroaryl ring (s) , provided that the heterocyclyl ring as a whole is not a heteroaryl ring, and the point of attachment can be on any ring. As used herein, the term "heterocyclylene" as used by itself or as part of another group refers to a divalent radical derived from the heterocyclyl group defined herein. The heterocyclyl or heterocylylene can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.
Exemplary non-limiting heterocyclyl groups include azirdinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl–2, 5–dione, dioxolanyl, oxasulfuranyl, disulfuranyl, oxazolidin-2-one, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinanyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
“Aryl” as used by itself or as part of another group refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ( “C
6–14 aryl” ) . In some embodiments, an aryl group has six ring carbon atoms ( “C
6 aryl” ; e.g., phenyl) . In some embodiments, an aryl group has ten ring carbon atoms ( “C
10 aryl” ; e.g., naphthyl such as 1–naphthyl and 2–naphthyl) . In some embodiments, an aryl group has fourteen ring carbon atoms ( “C
14 aryl” ; e.g., anthracyl) . As used herein, the term "arylene" as used by itself or as part of another group refers to a divalent radical derived from the aryl group defined herein.
“Aralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more aryl groups, preferably, substituted with one aryl group. Examples of aralkyl include benzyl, phenethyl, etc. When an aralkyl is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl can be optionally substituted.
“Heteroaryl” as used by itself or as part of another group refers to a radical of a 5–14 membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and at least one, preferably, 1–4, ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ( “5–14 membered heteroaryl” ) . In some embodiments, unless specified or otherwise contrary from context, the heteroaryl described herein can be a 5-10 membered heteroaryl, for example, a 5-or 6-membered heteroaryl, or 8-10 membered bicyclic heteroaryl. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. In bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) , the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl) . As used herein, the term "heteroarylene" as used by itself or as part of another group refers to a divalent radical derived from the heteroaryl group defined herein.
Exemplary non-limiting heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
“Heteroaralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more heteroaryl groups, preferably, substituted with one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.
An “optionally substituted” group, such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refers to the respective group that is unsubstituted or substituted. In general, the term “substituted” , whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position. Typically, when substituted, the optionally substituted groups herein can be substituted with 1-5 substituents. Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable. Two of the optional substituents can join to form a ring structure, such as an optionally substituted cycloalkyl, heterocylyl, aryl, or heteroaryl ring. Substitution can occur on any available carbon, oxygen, or nitrogen atom, and can form a spirocycle. Typically, substitution herein does not result in an O-O, O-N, S-S, S-N (except SO
2-N bond) , heteroatom-halogen, or -C (O) -Sbond or three or more consecutive heteroatoms, with the exception of O-SO
2-O, O-SO
2-N, and N-SO
2-N, except that some of such bonds or connections may be allowed if in a stable aromatic system.
In a broad aspect, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl) , a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , an alkoxy, a cycloalkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, an aryl, or a heteroaryl, each of which can be substituted, if appropriate.
Exemplary substituents include, but not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C (O) -aryl, halo, -NO
2, -CN, -SF
5, -C (O) OH, -C (O) O-alkyl, -C (O) O-aryl, -C (O) O-alkylene-aryl, -S (O) -alkyl, -S (O)
2-alkyl, -S (O) -aryl, -S (O)
2-aryl, -S (O) -heteroaryl, -S (O)
2-heteroaryl, -S-alkyl, -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) -NH
2, -C (═NH) -NH
2, -C (═NH) -NH (alkyl) , -N (Y
1) (Y
2) , -alkylene-N (Y
1) (Y
2) , -C (O) N (Y
1) (Y
2) and -S (O)
2N (Y
1) (Y
2) , wherein Y
1 and Y
2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.
Some examples of suitable substituents include, but not limited to, (C
1-C
8) alkyl groups, (C
2-C
8) alkenyl groups, (C
2-C
8) alkynyl groups, (C
3-C
10) cycloalkyl groups, halogen (F, Cl, Br or I) , halogenated (C
1-C
8) alkyl groups (for example but not limited to -CF
3) , -O- (C
1-C
8) alkyl groups, -OH, -S- (C
1-C
8) alkyl groups, -SH, -NH (C
1-C
8) alkyl groups, -N ( (C
1-C
8) alkyl)
2 groups, -NH
2, -C (O) NH
2, -C (O) NH (C
1-C
8) alkyl groups, -C (O) N ( (C
1-C
8) alkyl)
2, -NHC (O) H, -NHC (O) (C
1-C
8) alkyl groups, -NHC (O) (C
3-C
8) cycloalkyl groups, -N ( (C
1-C
8) alkyl) C (O) H, -N ( (C
1-C
8) alkyl) C (O) (C
1-C
8) alkyl groups, -NHC (O) NH
2, -NHC (O) NH (C
1-C
8) alkyl groups, -N ( (C
1-C
8) alkyl) C (O) NH
2 groups, -NHC (O) N ( (C
1-C
8) alkyl)
2 groups, -N ( (C
1-C
8) alkyl) C (O) N ( (C
1-C
8) alkyl)
2 groups, -N ( (C
1-C
8) alkyl) C (O) NH ( (C
1-C
8) alkyl) , -C (O) H, -C (O) (C
1-C
8) alkyl groups, -CN, -NO
2, -S (O) (C
1-C
8) alkyl groups, -S (O)
2 (C
1-C
8) alkyl groups, -S (O)
2N ( (C
1-C
8) alkyl)
2 groups, -S (O)
2NH (C
1-C
8) alkyl groups, -S (O)
2NH (C
3-C
8) cycloalkyl groups, -S (O)
2NH
2 groups, -NHS (O)
2 (C
1-C
8) alkyl groups, -N ( (C
1-C
8) alkyl) S (O)
2 (C
1-C
8) alkyl groups, - (C
1-C
8) alkyl-O- (C
1-C
8) alkyl groups, -O- (C
1-C
8) alkyl-O- (C
1-C
8) alkyl groups, -C (O) OH, -C (O) O (C
1-C
8) alkyl groups, NHOH, NHO (C
1-C
8) alkyl groups, -O-halogenated (C
1-C
8) alkyl groups (for example but not limited to -OCF
3) , -S (O)
2-halogenated (C
1-C
8) alkyl groups (for example but not limited to -S (O)
2CF
3) , -S-halogenated (C
1-C
8) alkyl groups (for example but not limited to -SCF
3) , - (C
1-C
6) heterocycle (for example but not limited to pyrrolidine, tetrahydrofuran, pyran or morpholine) , - (C
1-C
6) heteroaryl (for example but not limited to tetrazole, imidazole, furan, pyrazine or pyrazole) , -phenyl, -NHC (O) O- (C
1-C
6) alkyl groups, -N ( (C
1-C
6) alkyl) C (O) O- (C
1-C
6) alkyl groups, -C (═NH) - (C
1-C
6) alkyl groups, -C (═NOH) - (C
1-C
6) alkyl groups, or -C (═N-O- (C
1-C
6) alkyl) - (C
1-C
6) alkyl groups.
Exemplary carbon atom substituents include, but are not limited to, halogen, –CN, –NO
2, –N
3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkyl amino, dialkyl amino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C
3–10 carbocyclyl, C
6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl, etc. For example, exemplary carbon atom substituents can include F, Cl, -CN, –SO
2H, –SO
3H, –OH, –OC
1–6 alkyl, –NH
2, –N (C
1–6 alkyl)
2, –NH (C
1–6 alkyl) , –SH, –SC
1–6 alkyl, –C (=O) (C
1–6 alkyl) , –CO
2H, –CO
2 (C
1–6 alkyl) , –OC (=O) (C
1–6 alkyl) , –OCO
2 (C
1–6 alkyl) , –C (=O) NH
2, –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) , –NHCO
2 (C
1–6 alkyl) , –NHC (=O) N (C
1–6 alkyl)
2, –NHC (=O) NH (C
1–6 alkyl) , –NHC (=O) NH
2, –NHSO
2 (C
1–6 alkyl) , –SO
2N (C
1–6 alkyl)
2, –SO
2NH (C
1–6 alkyl) , –SO
2NH
2, –SO
2C
1–6 alkyl, –SO
2OC
1–6 alkyl, –OSO
2C
1–6 alkyl, –SOC
1–6 alkyl, C
1–6 alkyl, C
1–6 haloalkyl, C
2–6 alkenyl, C
2–6 alkynyl, C
3–10 carbocyclyl, C
6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl; or two geminal substituents can be joined to form =O.
Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfone, sulfoxide, C
1–10 alkyl, C
1–10 haloalkyl, C
2–10 alkenyl, C
2–10 alkynyl, C
3–10 carbocyclyl, 3–14 membered heterocyclyl, C
6–14 aryl, and 5–14 membered heteroaryl, or two substituent groups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group) . Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3
rd edition, John Wiley & Sons, 1999, incorporated by reference herein. Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl.
Exemplary oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, C
1–10 alkyl, C
1–10 haloalkyl, C
2–10 alkenyl, C
2–10 alkynyl, C
3–10 carbocyclyl, 3–14 membered heterocyclyl, C
6–14 aryl, and 5–14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group) . Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3
rd edition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM) , benzyloxymethyl (BOM) , 2–methoxyethoxymethyl (MEM) , etc., those forming silyl ethers, such as trymethylsilyl (TMS) , triethylsilyl (TES) , triisopropylsilyl (TIPS) , t-butyldimethylsilyl (TBDMS) , etc., those forming acetals or ketals, such as tetrahydropyranyl (THP) , those forming esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., those forming carbonates or sulfonates such as methanesulfonate (mesylate) , benzylsulfonate, and tosylate (Ts) , etc.
Unless expressly stated to the contrary, combinations of substituents and/or variables are allowable only if such combinations are chemically allowed and result in a stable compound. A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject) .
In some embodiments, the “optionally substituted” alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocyclic, carbocyclylene, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclyl, or heterocyclylene herein can each be independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, -OH, protected hydroxyl, oxo (as applicable) , NH
2, protected amino, NH (C
1-4 alkyl) or a protected derivative thereof, N (C
1-4 alkyl ( (C
1-4 alkyl) , C
1-4 alkyl, C
2-4 alkenyl, C
2-4 alkynyl, C
1-4 alkoxy, C
3-6 cycloalkyl, C
3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, -OH, oxo (as applicable) , C
1-4 alkyl, fluoro-substituted C
1-4 alkyl (e.g., CF
3) , C
1-4 alkoxy and fluoro-substituted C
1-4 alkoxy. In some embodiments, the “optionally substituted” aryl, arylene, heteroaryl or heteroarylene group herein can each be independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, -OH, -CN, NH
2, protected amino, NH (C
1-
4 alkyl) or a protected derivative thereof, N (C
1-4 alkyl ( (C
1-4 alkyl) , –S (=O) (C
1-4 alkyl) , –SO
2 (C
1-4 alkyl) , C
1-4 alkyl, C
2-4 alkenyl, C
2-4 alkynyl, C
1-4 alkoxy, C
3-6 cycloalkyl, C
3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2 or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, -OH, oxo (as applicable) , C
1-4 alkyl, fluoro-substituted C
1-4 alkyl, C
1-4 alkoxy and fluoro-substituted C
1-4 alkoxy.
“Halo” or “halogen” refers to fluorine (fluoro, –F) , chlorine (chloro, –Cl) , bromine (bromo, –Br) , or iodine (iodo, –I) .
The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from tautomerization. The exact ratio of the tautomers depends on several factors, including for example temperature, solvent, and pH. Tautomerizations are known to those skilled in the art. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to- (adifferent enamine) tautomerizations.
The term “subject” (alternatively referred to herein as “patient” ) as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
As used herein, the terms "treat, " "treating, " "treatment, " and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms "treat, " "treating, " "treatment, " and the like may include "prophylactic treatment, " which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.
The term "effective amount" refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, prophylaxis or treatment of diseases. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo) , or the subject and disease condition being treated (e.g., the weight, age and gender of the subject) , the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells and/or tissues. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.
As used herein, the singular form “a” , “an” , and “the” , includes plural references unless it is expressly stated or is unambiguously clear from the context that such is not intended.
The term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone) ; and B (alone) . Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone) ; B (alone) ; and C (alone) .
Headings and subheadings are used for convenience and/or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.
Examples
The various starting materials, intermediates, and compounds of embodiments herein can be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. The abbreviations used in the Examples section should be understood as having their ordinary meanings in the art unless specifically indicated otherwise or obviously contrary from context. The examples are illustrative only and do not limit the claimed invention in any way.
Exemplary embodiments of steps for performing the synthesis of products described herein are described in greater detail infra. Some of the Examples discussed herein can be prepared by separating the corresponding racemic mixtures. As would be understood by a person of ordinary skill in the art, the compounds described in the Examples section immmmediately prior to the chiral separation step, e.g., by supercritical fluid chromatography (SFC) , exist in racemic and/or stereoisomeric mixture forms, the bolded but not wedged bonds are used in the chemical structure drawings to indicate relative stereochemistry. It should be understood that the enantiomeric excesses ( "ee" ) reported for these examples are only representative from the exemplified procedures herein and not limiting; those skilled in the art would understand that such enantiomers with a different ee, such as a higher ee, can be obtained in view of the present disclosure.
Synthesis of benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (Intermediate A)
To a solution of methyl 3-oxocyclopentane-1-carboxylate (1, 10.0 g, 70.3 mmol) and ethylene glycol (6.60 g, 105 mmol) in toluene (80 mL) was added p-toluenesulfonic acid monohydrate (1.20 g, 1.03 mmol) . The reaction mixture was stirred and heated to reflux with a Dean-Stark trap for 15 hrs. The solvent was removed under reduced pressure to give a residue. The residue was redissolved with ethyl acetate (250 mL) , washed with water (50 mL x 3) , dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography to afford methyl 1, 4-dioxaspiro [4.4] nonane-7-carboxylate (2, 5.30 g, 40%) as a colorless oil. LC-MS (ESI) : m/z 187 [M+H]
+.
To a solution of n-butyllithium (22.8 mL, 56.9 mmol, 2.5 M in Hexane) in tetrahydrofuran (30 mL) was added acetonitrile (2.34 g, 56.9 mmol) dropwise at -65 ℃under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 1 hr. A solution of methyl 1, 4-dioxaspiro [4.4] nonane-7-carboxylate (2, 5.30 g, 28.4 mmol) in tetrahydrofuran (15 mL) was added dropwise to the reaction mixture, and the resulting mixture was stirred at -65 ℃ for additional 1 hr. The reaction mixture was quenched with water (20 mL) , adjusted to pH 7 with 1 M aq. HCl and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3-oxo-3- (1, 4-dioxaspiro [4.4] nonan-7-yl) propanenitrile (3, 5.35 g, 96%) as a colorless oil, which was used in next step without further purification. LC-MS (ESI) : m/z 196 [M+H]
+.
To a suspension of tert-butylhydrazine hydrochloride (2.68 g, 30.4 mmol) in ethyl alcohol (40 mL) was added sodium hydroxide (1.22 g, 30.43 mmol) in portions, and the reaction mixture was stirred at 25 ℃ for 1 hr. A solution of 3-oxo-3- (1, 4-dioxaspiro [4.4] nonan-7-yl) propanenitrile (3, 4.95 g, 25.3 mmol) in ethyl alcohol (10 mL) was added to the reaction mixture, and the resulting mixture was stirred at 80 ℃ for 24 hrs. 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 to afford 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-amine (4, 4.00 g, 59%) as a colorless oil. LC-MS (ESI) : m/z 266 [M+H]
+.
To a mixture of 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-amine (4, 3.50 g, 13.2 mmol) and sodium bicarbonate (3.55 g, 42.2 mmol) in acetonitrile (30 mL) was added benzyl chloroformate (4.50 g, 26.4 mmol) dropwise. The reaction mixture was stirred at 25 ℃ for 18 hrs. The mixture was quenched with water (20 mL) , adjusted to pH 7 with 1 M aq. HCl and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) carbamate (5, 4.00 g, 76%) as a colorless oil. LC-MS (ESI) : m/z 400 [M+H]
+.
To a solution of (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) carbamate (5, 4.00 g, 10.0 mmol) in acetone (10 mL) and water (10 mL) was added p-toluenesulfonic acid monohydrate (345 mg, 2.00 mmol) . The reaction mixture was stirred at 60 ℃ for 18 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with dichloromethane (80 mL) , washed with saturated solution of sodium bicarbonate (30 mL) and brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography to afford benzyl (1- (tert-butyl) -3- (3-oxocyclopentyl) -1H-pyrazol-5-yl) carbamate (6, 3.20 g, 90%) as a white solid. LC-MS (ESI) : m/z 356 [M+H]
+.
To a solution of (1- (tert-butyl) -3- (3-oxocyclopentyl) -1H-pyrazol-5-yl) carbamate (6, 3.20 g, 9.00 mmol) in tetrahydrofuran (30 mL) was added lithium triethylborohydride (18 mL, 18 mmol, 1 M in tetrahydrofuran) dropwise at -65 ℃ under nitrogen atmosphere. The reaction mixture was stirred at -65 ℃ for 1.5 hrs. The mixture was quenched with saturated solution of sodium bicarbonate (15 mL) at -30 ℃, followed by hydrogen peroxide (30%aqueous solution, 7 mL) at -10 ℃, and the resulting mixture was stirred at 10 ℃ for additional 1 hr. The aqueous layer was extracted with ethyl acetate (20 mL x 3) , and the combined organic layers were washed with saturated solution of sodium sulfite (20 mL) and brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-benzyl (1- (tert-butyl) -3- (3-hydroxycyclopentyl) -1H-pyrazol-5-yl) carbamate (7a, 2.40 g, 75%) as a white solid and trans-benzyl (1- (tert-butyl) -3- (3-hydroxycyclopentyl) -1H-pyrazol-5-yl) carbamate (7b, 480 mg, 15%) as a white solid.
7a: LC-MS (ESI) : m/z 358 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 9.05 (s, 1H) , 7.37 -7.31 (m, 5H) , 5.92 (s, 1H) , 5.11 (s, 2H) , 4.57 (d, J = 4.4 Hz, 1H) , 4.14 -4.10 (m, 1H) , 2.90 -2.86 (m, 1H) , 2.21 -2.12 (m, 1H) , 1.90 -1.52 (m, 4H) , 1.47 (s, 9H) , 1.52 -1.43 (m, 1H) .
cis-benzyl (1- (tert-butyl) -3- (3-hydroxycyclopentyl) -1H-pyrazol-5-yl) carbamate (7a, 2.20 g) was separated by Chiral SFC to afford benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) carbamate (8a, 900 mg, P1, []
D
20 = +3.5, c = 0.74 in methanol) as a white solid and benzyl (1- (tert-butyl) -3- ( (1R, 3S) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) carbamate (8a’, 1.00 g, P2, []
D
20 = -1.82, c = 0.82 in methanol) as a white solid. LC-MS (ESI) : m/z 358 [M+H]
+.
The absolute configurations of 8a and 8a’ were assigned in accordance with patent US11014911 B2.
SFC method: IC-H, 4.6*250 mm; IPA 0.05%, DEA 40%; 8 min.
To a solution of benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) carbamate (8a, 300 mg, 0.84 mmol) in dichloromethane (10 mL) were added 4-nitrophenyl carbonochloridate (340 mg, 1.70 mmol) and pyridine (200 mg, 2.50 mmol) at 0 ℃. The resulting mixture was warmed to room temperature and stirred for 14 hrs. Then it was quenched with water (10 mL) , adjusted to pH 7 with 1 M HCl and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (Intermediate A, 330 mg, 75%) as a pale yellow solid. LC-MS (ESI) : m/z 523 [M+H]
+.
Synthesis of (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (Intermediate B)
To a solution of benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (Intermediate A, 300 mg, 0.57 mmol) in tetrahydrofuran (5 mL) were added isopropyl amine (45.0 mg, 0.74 mmol) and N, N-diisopropylethylamine (370 mg, 2.85 mmol) . The mixture was stirred at room temperature for 14 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (9, 220 mg, 87%) as a white solid. LC-MS (ESI) : m/z 443 [M+H]
+.
To a solution of benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (9, 220 mg, 0.50 mmol) in ethyl alcohol (5 mL) was added palladium (10%on carbon, 50.0 mg) . The resulting mixture was degassed and backfilled with H
2 three times, and stirred at room temperature under H
2 atmosphere (1 atm) for 14 hrs. 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 to afford (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (Intermediate B, 130 mg, 84%) as a pale yellow solid. LC-MS (ESI) : m/z 309 [M+H]
+.
Synthesis of 4-chloro-2- (methoxymethyl) pyrazolo [1, 5-a] pyrazine (Intermediate C)
To a solution of dimethyl 1H-pyrazole-3, 5-dicarboxylate (10, 2.60 g, 14.1 mmol) in tetrahydrofuran (80 mL) was added sodium hydride (1.12 g, 28.2 mmol, 60%suspended in mineral oil) at 0 ℃ under nitrogen atmosphere, and the mixture was stirred at 0 ℃ for 30 min. 2-chloromethyl 2- (trimethylsilyl) ethyl ether (3.50 g, 21.1 mmol) was added to the reaction mixture was added and stirred at 0 ℃ for additional 30 min. The resulting mixture was warmed to room temperature and stirred for 14 hrs. The reaction mixture was quenched with water (10 mL) , adjusted to pH 7 with 1 M aq. HCl and extracted with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford dimethyl 1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3, 5-dicarboxylate (11, 2.60 g, 59%) as a colorless oil. LC-MS (ESI) : m/z 315 [M+H]
+.
To a solution of dimethyl 1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3, 5-dicarboxylate (11, 2.60 g, 8.30 mmol) in methanol (50 mL) and water (10 mL) was added lithium hydroxide monohydrate (710 mg, 16.6 mmol) , and the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was adjusted to pH 6-7 with 1 M aq. HCl and extracted with ethyl acetate (30 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 5- (methoxycarbonyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3-carboxylic acid (12, 2.10 g, 84%) as a colorless oil. LC-MS (ESI) : m/z 301 [M+H]
+.
To a solution of 5- (methoxycarbonyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3-carboxylic acid (12, 2.10 g, 7.00 mmol) in dichloromethane (40 mL) were added N, N-dimethylformamide (2 drops) and oxalyl chloride (1.33 g, 10.5 mmol) dropwise at 0 ℃. The resulting mixture was warmed to room temperature and stirred for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford methyl 3- (chlorocarbonyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (13, 2.20 g, crude) , which was used in next step without further purification.
To a solution of methyl 3- (chlorocarbonyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (13, 2.20 g, crude) in methanol (30 mL) was added sodium borohydride (530 mg, 14.0 mmol) in portions over 30 mins. The resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford methyl 3- (hydroxymethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (14, 1.20 g, 60%yield from 12) as a colorless oil. LC-MS (ESI) : m/z 287 [M+H]
+.
To a solution of methyl 3- (hydroxymethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (14, 1.20 g, 4.20 mmol) in dichloromethane (30 mL) were added triethylamine (840 mg, 8.40 mmol) and methanesulfonyl chloride (720 mg, 6.30 mmol) at 0 ℃. The resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford methyl 3- ( ( (methylsulfonyl) oxy) methyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (15, 1.10 g, 72%) as a white solid. LC-MS (ESI) : m/z 365 [M+H]
+.
To a solution of methyl 3- ( ( (methylsulfonyl) oxy) methyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (15, 1.10 g, 3.00 mmol) in methanol (30 mL) was added sodium methoxide (810 mg, 15.0 mmol) in portions. The resulting mixture was stirred at room temperature for 14 hrs. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford methyl 3- (methoxymethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (16, 800 mg, 89%) as a light yellow oil. LC-MS (ESI) : m/z 301 [M+H]
+.
To a solution of methyl 3- (methoxymethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (16, 800 mg, 2.60 mmol) in methanol (50 mL) and water (10 mL) was added lithium hydroxide monohydrate (210 mg, 5.20 mmol) . The resulting mixture was stirred at room temperature for 14 hrs. The reaction mixture was adjusted to pH 6-7 with 1 M aq. HCl and extracted with ethyl acetate (30 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 3- (methoxymethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylic acid (17, 700 mg, 94%) as a white solid. LC-MS (ESI) : m/z 285 [M-H]
-.
To a solution of 3- (methoxymethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylic acid (17, 700 mg, 2.45 mmol) in N, N-dimethylformamide (10 mL) were added 2- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (1.02 g, 2.70 mmol) , 2, 2-dimethoxyethan-1-amine (570 mg, 5.40 mmol) and triethylamine (540 mg, 5.40 mmol) . The resulting mixture was stirred at room temperature for 1 hr. The mixture was added water (20 mL) and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford N- (2, 2-dimethoxyethyl) -3- (methoxymethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxamide (18, 650 mg, 71%) as white solid. LC-MS (ESI) : m/z 374 [M+H]
+.
To a solution of N- (2, 2-dimethoxyethyl) -3- (methoxymethyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxamide (18, 650 mg, 1.74 mmol) in tetrahydrofuran (30 mL) was added concentrated hydrochloric acid (10 mL) . The resulting mixture was stirred at room temperature for 14 hrs. The reaction mixture was adjusted to pH 7-8 with saturated solution of sodium bicarbonate and extracted with ethyl acetate (30 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 7-hydroxy-2- (methoxymethyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one (19, 150 mg, 44%) as a brown solid. LC-MS (ESI) : m/z 198 [M+H]
+.
A mixture of 7-hydroxy-2- (methoxymethyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one (19, 150 mg, 0.76 mmol) and methanesulfonic acid (3 mL) was stirred at 50 ℃for 14 hrs. The reaction mixture was concentrated under reduced pressure to afford 2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-ol (20, 150 mg, crude) , which was used in next step without further purification. LC-MS (ESI) : m/z 180 [M+H]
+.
A mixture of 2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-ol (20, 150 mg, crude) and phosphorus oxychloride (2 mL) was heated to reflux and stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was adjusted to pH 7-8 with saturated solution of sodium bicarbonate and extracted with ethyl acetate (5 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to prep-TLC to afford 4-chloro-2- (methoxymethyl) pyrazolo [1, 5-a] pyrazine (Intermediate C, 50.0 mg, 27%yield from 19) as a grey solid. LC-MS (ESI) : m/z 198 [M+H]
+ .
Synthesis of 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxylic acid (Intermediate D)
To a mixture of 3-oxocyclopentane-1-carboxylic acid (21, 10.0 g, 78.0 mmol) , 2- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (44.5 g, 117 mmol) and N, O-dimethylhydroxylamine hydrochloride (9.90 g, 101 mmol) in N, N-dimethylformamide (100 mL) was added diisopropylethylamine (30.2 g, 234 mmol) at 0 ℃. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (150 mL x 3) . The organic layer was washed with brine (50 mL x 3) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford N-methoxy-N-methyl-3-oxocyclopentane-1-carboxamide (22, 13.1 g, 97%) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ 3.71 (s, 3H) , 3.58 -3.39 (m, 1H) , 3.20 (s, 3H) , 2.59 -2.04 (m, 6H) .
A mixture of N-methoxy-N-methyl-3-oxocyclopentane-1-carboxamide (22, 5.00 g, 29.2 mmol) , ethane-1, 2-diol (1.80 mL, 32.1 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.92 mmol) in toluene (65 mL) was stirred at 130 ℃ for 4 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford N-methoxy-N-methyl-1, 4-dioxaspiro [4.4] nonane-7-carboxamide (23, 3.20 g, 51%) as a yellow oil.
1H NMR (400 MHz, DMSO-d
6) δ 3.93 -3.82 (m, 4H) , 3.65 (s, 3H) , 3.30 -3.17 (m, 1H) , 3.15 (s, 3H) , 2.13 -1.71 (m, 6H) .
To a solution of N-methoxy-N-methyl-1, 4-dioxaspiro [4.4] nonane-7-carboxamide (23, 3.20 g, 14 . 866 mmol) in tetrahydrofuran (70 mL) was added methylmagnesium bromide (30 mL, 29.7 mmol, 1 M in tetrahydrofuran) dropwise at -60 ℃ under nitrogen atmosphere. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aq. NH
4Cl (50 mL) at 0 ℃ and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 1- (1, 4-dioxaspiro [4.4] nonan-7-yl) ethan-1-one (24, 2.00 g , 75%) as a colorless oil.
1H NMR (400 MHz, DMSO-d
6) δ 3.94 -3.81 (m, 4H) , 3.04 -2.92 (m, 1H) , 2.14 (s, 3H) , 2.07 -1.75 (m, 6H) .
To a solution of 1- (1, 4-dioxaspiro [4.4] nonan-7-yl) ethan-1-one (24, 2.00 g, 11.7 mmol) in tetrahydrofuran (30 mL) was added lithium hexamethyldisilazide (15.2 mL, 15.2 mmol) dropwise at -60 ℃ under nitrogen atmosphere. The mixture was stirred at -60 ℃ for 1 hr. To the reaction mixture was added a solution of dimethyl oxalate (2.08 g, 17.6 mmol) in tetrahydrofuran (30 mL) dropwise at -60 ℃ and the resulting mixture was stirred at room temperature for 4 hrs. It was quenched with saturated aq. NH
4Cl (50 mL) at 0 ℃ and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford methyl 2, 4-dioxo-4- (1, 4-dioxaspiro [4.4] nonan-7-yl) butanoate (25, 1.95 g, 66%) as a colorless oil. LC-MS (ESI) : m/z 257.1 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 6.38 (s, 1H) , 3.94 -3.89 (m, 4H) , 3.87 (s, 3H) , 3.13 -2.96 (m, 1H) , 2.14 -1.81 (m, 6H) .
To a solution of tert-butylhydrazine hydrochloride (1.26 g, 10.1 mmol) in methanol (40 mL) and water (2 mL) was added sodium bicarbonate (0.85 g, 10.1 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred for 1 hr. To the reaction mixture was added ethyl 2, 4-dioxo-4- (1, 4-dioxaspiro [4.4] nonan-7-yl) butanoate (25, 2.60 g, 10.1 mmol) dropwise, and the resulting solution was heated to 80 ℃ and stirred for 1 hr. It was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford methyl 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxylate (26, 1.27 g, 41%) as a colorless oil. LC-MS (ESI) : m/z 309.2 [M+H]
+.
To a solution of methyl 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxylate (26, 1.27 g, 4.12 mmol) in water (15 mL) was added lithium hydroxide (0.35 g, 8.23 mmol) at 0 ℃. The mixture was heated to 80 ℃ and stirred for 2 hrs. The reaction mixture was poured into ice water (20 mL) , adjusted to pH 2 with aq. HCl (20 mL, 0.5 M) at 0 ℃ and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxylic acid (Intermediate D, 1.02 g, 82%) as a white solid. LC-MS (ESI) : m/z 295.2 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.44 (s, 1H) , 6.67 (s, 1H) , 3.89 -3.81 (m, 4H) , 3.64 -3.52 (m, 1H) , 2.28 -2.18 (m, 1H) , 2.16 -2.06 (m, 1H) , 2.04 -1.95 (m, 1H) , 1.85 -1.67 (m, 3H) , 1.60 (s, 9H) .
Synthesis of (1R, 3S) -3- (5- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (I)
A mixture of (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (Intermediate B, 130 mg, 0.42 mmol) , 4-chloro-2- (methoxymethyl) pyrazolo [1, 5-a] pyrazine (Intermediate C, 85.0 mg, 0.42 mmol) , cesium carbonate (410 mg, 1.26 mmol) , palladium (II) acetate (20.0 mg, 0.08 mmol) and xantphos (49.0 mg, 0.08 mmol) in dioxane (5 mL) was degassed and backfilled with nitrogen three times. The mixture was sealed in a microwave tube and stirred at 100 ℃under microwave irradiation for 1 hr. 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 to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (I-1, 50.0 mg, 24%) as a white solid. LC-MS (ESI) : m/z 470 [M+H]
+.
A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (I-1, 50.0 mg, 0.11 mmol) in formic acid (10 mL) was stirred at 60 ℃ for 14 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was subjected to prep-HPLC to afford (1R, 3S) -3- (5- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (I, 12.0 mg, 26%) as a white solid. LC-MS (ESI) : m/z 414 [M+H]
+.
1H NMR (400 MHz, CD
3OD-d
4) δ 8.18 (d, J = 4.8 Hz, 1H) , 7.43 (d, J = 5.2 Hz, 1H) , 7.38 (s, 1H) , 6.23 (s, 1H) , 5.17 -5.08 (m, 1H) , 4.69 (s, 2H) , 3.56 -3.42 (m, 1H) , 3.45 (s, 3H) , 3.30 -3.20 (m, 1H) , 2.62 -2.55 (m, 1H) , 2.22 -2.16 (m, 1H) , 2.01 -1.83 (m, 4H) , 1.07 -1.16 (m, 6H) .
Synthesis of (1R, 3S) -3- (3- ( (2- (methoxymethyl) -3-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (II)
A mixture of dimethyl 1H-pyrazole-3, 5-dicarboxylate (II-1, 8.00 g, 43.4 mmol) , N-bromosuccinimide (9.28 g, 52.1 mmol) , concentrated nitric acid (0.6 mL) and acetic acid (11.4 mL) was heated to 120 ℃ under microwave irradiation for 30 mins. The reaction mixture was quenched with saturated solution of sodium bicarbonate (100 mL) at 0 ℃ and extracted with ethyl acetate (100 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give dimethyl 4-bromo-1H-pyrazole-3, 5-dicarboxylate (II-2, 11.4 g, crude) , which was used in next step without further purification. LC-MS (ESI) : m/z 263 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 12.48 (s, 1H) , 3.96 (s, 6H) .
To a solution of dimethyl 4-bromo-1H-pyrazole-3, 5-dicarboxylate (II-2, 14.0 g, crude) in tetrahydrofuran (150 mL) was added sodium hydride (2.55 g, 63.8 mmol) in portions at 0 ℃ under nitrogen atmosphere. The mixture was stirred at 0 ℃ for 30 mins. To the reaction mixture was added (2- (Chloromethoxy) ethyl) trimethylsilane (13.3 g, 79.8 mmol) dropwise, and the resulting mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was quenched with saturated solution of ammonium chloride (120 mL) at 0 ℃ and extracted with ethyl acetate (120 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford dimethyl 4-bromo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3, 5-dicarboxylate (II-3, 18.8 g, 89%yield from 2) as a colorless oil. LC-MS (ESI) : m/z 393 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 5.87 (s, 2H) , 3.98 (s, 3H) , 3.97 (s, 3H) , 3.63 -3.48 (m, 2H) , 0.89 -0.83 (m, 2H) , 0.03 (s, 9H) .
To a mixture of 4-bromo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3, 5-dicarboxylate (II-3, 5.00 g, 12.7 mmol) and 2, 4, 6-trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane (21.8 mL, 76.3 mmol, 3.5 M in tetrahydrofuran) in N, N-dimethylformamide (50 mL) were added potassium carbonate (5.27 g, 38.1 mmol) and [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.93 g, 1.271 mmol) . The reaction mixture was degassed and backfilled with nitrogen three times, and stirred at 110 ℃ under N
2 atmosphere for 5 hrs. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (200 mL) , washed with brine (80 mL x 2) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford dimethyl 4-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3, 5-dicarboxylate (II-4, 3.48 g, 83%) as a yellow oil. LC-MS (ESI) : m/z 329 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 5.85 (s, 2H) , 3.93 (s, 6H) , 3.55 (t, J = 8.4 Hz, 2H) , 2.54 (s, 3H) , 0.86 (t, J = 8.4 Hz, 2H) , 0.04 (s, 9H) .
To a solution of dimethyl 4-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-3, 5-dicarboxylate (II-4, 2.65 g, 8.06 mmol) in methanol (30 mL) was added sodium borohydride (2.73 g, 80.7 mmol) in portions at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 mins. The reaction mixture was quenched with water (30 mL) at 5 ℃and extracted with ethyl acetate (30 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford methyl 3- (hydroxymethyl) -4-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (II-5, 2.20 g, 91%) as a colorless oil. LC-MS (ESI) : m/z 301 [M+H]
+.
To a solution of methyl 3- (hydroxymethyl) -4-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (II-5, 2.20 g, 7.32 mmol) in dichloromethane (30 mL) were added triethylamine (1.53 mL, 10.9 mmol) and methanesulfonyl chloride (1.01 g, 8.78 mmol) at 0 ℃. The mixture was stirred at room temperature for 2 hrs. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (30 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 4-methyl-3- ( ( (methylsulfonyl) oxy) methyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (II-6, 2.30 g, 82%) as a yellow oil. LC-MS (ESI) : m/z 379 [M+H]
+.
To a solution of 4-methyl-3- ( ( (methylsulfonyl) oxy) methyl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylate (II-6, 2.30 g, 6.07 mmol) in methanol (30 mL) was added sodium methoxide (6.80 mL, 36.4 mmol, 5.30 M in methanol) at 0 ℃. The mixture was stirred at room temperature for 15 hrs. To the reaction mixture was added water (10 mL) and the resulting mixture was stirred for additional 2 hrs. The mixture was concentrated under reduced pressure, redissolved with ethyl acetate (50 mL) , adjusted to pH ~ 2 with 1 M HCl and extracted with ethyl acetate (40 mL x 3) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 3- (methoxymethyl) -4-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylic acid (II-7, 1.40 g, 76%) as a yellow oil. LC-MS (ESI) : m/z 301 [M+H]
+.
A mixture of 3- (methoxymethyl) -4-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxylic acid (II-7, 1.40 g, 4.66 mmol) , 2, 2-dimethoxyethan-1-amine (0.54 g, 5.12 mmol) , 2- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (1.95 g, 5.12 mmol) and triethylamine (1.30 mL, 9.32 mmol) in N, N-dimethylformamide (15 mL) was stirred at room temperature for 15 hrs. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford N- (2, 2-dimethoxyethyl) -3- (methoxymethyl) -4-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxamide (II-8, 1.38 g, 76%) as a yellow oil. LC-MS (ESI) : m/z 388 [M+H]
+.
To a solution of N- (2, 2-dimethoxyethyl) -3- (methoxymethyl) -4-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-5-carboxamide (II-8, 1.38 g, 3.56 mmol) in tetrahydrofuran (10 mL) was added 5 M HCl aqueous solution (10 mL) . The resulting mixture was stirred at 0 ℃ for 2 hrs. To the reaction mixture was added water (20 mL) and the mixture was extracted with dichloromethane (30 mL x 6) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 7-hydroxy-2- (methoxymethyl) -3-methyl-6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one (II-9, 110 mg, 15%) as a white solid. LC-MS (ESI) : m/z 212 [M+H]
+.
A solution of 7-hydroxy-2- (methoxymethyl) -3-methyl-6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one (II-9, 100 mg, 0.47 mmol) in methanesulfonic acid (5 mL) was stirred at 48 ℃ for 14hrs. The reaction mixture was quenched with water (5 mL) at 0 ℃, adjusted to pH 7-8 with saturated solution of sodium bicarbonate and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 2- (methoxymethyl) -3-methylpyrazolo [1, 5-a] pyrazin-4 (5H) -one (II-10, 50.0 mg, 55%) as a white solid. LC-MS (ESI) : m/z 194 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 11.00 (s, 1H) , 7.51 (d, J = 5.8 Hz, 1H) , 6.77-6.73 (m, 1H) , 4.46 (s, 2H) , 3.25 (s, 3H) , 2.36 (s, 3H) .
To a solution of 2- (methoxymethyl) -3-methylpyrazolo [1, 5-a] pyrazin-4 (5H) -one (II-10, 70.0 mg, 0.36 mmol) in phosphorus oxychloride (3 mL) was added N, N-dimethylaniline (44 mg, 0.36 mmol) . The reaction mixture was stirred at 85 ℃ for 2 hrs. The resulting mixture was concentrated under reduced pressure, redissolved with ethyl acetate (15 mL) , poured into saturated solution of sodium bicarbonate (10 mL) and then extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 4-chloro-2- (methoxymethyl) -3-methylpyrazolo [1, 5-a] pyrazine (II-11, 50.0 mg, 65%) as a white solid. LC-MS (ESI) : m/z 212 [M+H]
+.
A mixture of 4-chloro-2- (methoxymethyl) -3-methylpyrazolo [1, 5-a] pyrazine (II-11, 50.0 mg, 0.23 mmol, ) , (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (Intermediate B, 71.0 mg, 0.23 mmol) , palladium (Ⅱ) acetate (16 mg, 0.069 mmol) , xantphos (41.0 mg, 0.07 mmol) and cesium carbonate (231 mg, 0.69 mmol) in dioxane (3 mL) was degassed and backfilled with N
2 three times. It was sealed in a microwave tube and stirred at 70 ℃ under microwave irradiation for 1.5 hrs. The resulting mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (2- (methoxymethyl) -3-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (II-12, 30.0 mg, 26%) as a white solid. LC-MS (ESI) : m/z 484 [M+H]
+.
A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2- (methoxymethyl) -3-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (II-12, 30.0 mg, 0.06 mmol) in formic acid (5 mL) was stirred at 60 ℃ for 12 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was subjected to prep-HPLC to afford (1R, 3S) -3- (3- ( (2- (methoxymethyl) -3-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (II, 6.00 mg, 22%, 100%ee) as a white solid. LC-MS (ESI) : m/z 428 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.32 -11.48 (m, 2H) , 8.35 -7.94 (m, 1H) , 7.34 -7.24 (m, 1H) , 7.00 -6.87 (m, 1H) , 6.51 & 5.88 (s, 1H) , 5.08 -4.93 (m, 1H) , 4.54 & 4.45 (s, 2H) , 3.65 -3.51 (m, 1H) , 3.27 & 3.26 (s, 3H) , 3.16 -3.02 (m, 1H) , 2.52 & 2.47 (s, 3H) , 2.47 -2.44 (m, 1H) , 2.09 -2.00 (m, 1H) , 1.96 -1.85 (m, 1H) , 1.80 -1.62 (m, 3H) , 1.05 -0.96 (m, 6H) .
Retention time: 1.654 min.
SFC Method: Column: ChiralPak C-IG, 100×4.6 mm I.D., 5 μm; Mobile phase: A for CO
2 and B for Isopropyl alcohol (0.05%DEA) ; Gradient: 8 min @40%B; Flow rate: 2.5 mL/min; Column temperature: 40 ℃.
Synthesis of (1R, 3S) -3- (3- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl cyclopropylcarbamate (III)
To a solution of benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (Intermediate A, 130 mg, 0.24 mmol) in tetrahydrofuran (3 mL) were added cyclopropanamine (18.0 mg, 0.32 mmol) and diisopropylethylamine (161 mg, 1.24 mmol) . The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (cyclopropylcarbamoyl) oxy) cyclopentyl) - 1H-pyrazol-5-yl) carbamate (III-1, 100 mg, 91%) as a white solid. LC-MS (ESI) : m/z 441.1 [M+H]
+.
To a solution of benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (cyclopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) carbamate (III-1, 60.0 mg, 0.13 mmol) in ethyl acetate (5 mL) and tetrahydrofuran (5 mL) was added palladium (10%on carbon, 20.0 mg) . The mixture was degassed and backfilled with H
2 three times, and stirred at room temperature under H
2 atmosphere (1 atm) for 3 hrs. 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 to afford (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl cyclopropylcarbamate (III-2, 40.0 mg, 67%) as a pale yellow solid. LC-MS (ESI) : m/z 307.1 [M+H]
+.
A mixture of (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl cyclopropylcarbamate (III-2, 49.0 mg, 0.16 mmol) , 4-chloro-2- (methoxymethyl) pyrazolo [1, 5-a] pyrazine (Intermediate C, 32.0 mg, 0.16 mmol) , cesium carbonate (156 mg, 0.48 mmol) , palladium (II) acetate (15.0 mg, 0.06 mmol) and xantphos (15.0 mg, 0.02 mmol) in dioxane (3 mL) was degassed and backfilled with N
2 three times. The mixture was sealed in a microwave tube and stirred at 100 ℃ under microwave irradiation for 1 hr. 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 to afford (1R, 3S) -3- (1- (tert-butyl) -5- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl cyclopropylcarbamate (III-3, 12.0 mg, 16%) as a white solid. LC-MS (ESI) : m/z 468.1 [M+H]
+.
A solution of (1R, 3S) -3- (1- (tert-butyl) -5- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl cyclopropylcarbamate (III-3, 12.0 mg, 0.03 mmol) in formic acid (3 mL) was stirred at 50 ℃ for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was subjected to prep-HPLC to afford (1R, 3S) -3- (3- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl cyclopropylcarbamate (III, 4.00 mg, 37%) as white solid. LC-MS (ESI) : m/z 412.3 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) (tautomer ratio ~ 2: 1) δ 12.21 -11.32 (m, 2H) , 7.76 -7.55 (m, 1H) , 7.33 -7.06 (m, 3H) , 6.22 -6.07 (m, 1H) , 5.26 -4.98 (m, 1H) , 4.60 & 4.59 (s, 2H) , 3.38 & 3.35 (s, 3H) , 3.06 -2.84 (m, 1H) , 2.55 -2.36 (m, 1H) , 2.30 -1.68 (m, 6H) , 0.59 -0.45 (m, 2H) , 0.40 -0.23 (m, 2H) .
Synthesis of cis-3- (3- (6- (methoxymethyl) -4-methyl-1H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (IV) and cis-3- (3- (6- (methoxymethyl) -4-methyl-1H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (V)
2, 6-dichloropyridin-4-amine (IV-1, 10.0 g, 61.3 mmol) was added to concentrated sulfuric acid (100 mL) in portions at -10 ℃. The mixture was warmed to 0 ℃, added concentrated nitric acid (30 mL) dropwise and stirred at 0 ℃ for 2 hrs. The reaction mixture was poured into ice water (1 L) and a suspension was formed. The suspension was stirred at 0 ℃ for 30 mins, then filtered, and the filter cake was dried in vacuum to afford N- (2, 6-dichloropyridin-4-yl) nitramide (IV-2, 11.2 g, 88%) as a white solid. LC-MS (ESI) : m/z 208.1 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.46 (s, 2H) .
N- (2, 6-dichloropyridin-4-yl) nitramide (IV-2, 11.2 g, 53.8 mmol) was added to concentrated sulfuric acid (100 ml) in portions at -40 ℃. The mixture was heated to 100 ℃ and stirred for 1 hr. The reaction mixture was poured into ice water (1 L) , adjusted to pH 9-10 with 6 M aq. NaOH and stirred at room temperature for additional 30 mins. A precipitation was formed and the solid was collected by filtration. The filter cake was dried in vacuum to afford 2, 6-dichloro-3-nitropyridin-4-amine (IV-3, 8.50 g, 76%) as a white solid. LC-MS (ESI) : m/z 208.2 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.65 (s, 2H) , 6.88 (s, 1H) .
To a mixture of 2, 6-dichloro-3-nitropyridin-4-amine (IV-3, 15.0 g, 33.6 mmol) and tetrakis (triphenylphosphine) palladium (0) (4.28 g, 3.70 mmol) in N, N-dimethylformamide (150 mL) was added trimethylaluminium (18.5 mL, 37.0 mmol, 2 M in toluene) dropwise. The reaction mixture was degassed and backfilled with N
2 three times, and stirred at 70 ℃ under N
2 atmosphere for 3 hrs. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with ice water (50 mL) , adjusted to pH 10 with saturated aq. Na
2CO
3 at 0 ℃ and extracted with ethyl acetate (200 mL x 3) . The combined organic layers were washed with brine (200 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 4-amino-6-methyl-5-nitropicolinonitrile (IV-4, 10.1 g, 74%) as a yellow solid. LC-MS (ESI) : m/z 188.1 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 6.63 (s, 1H) , 5.93 (s, 2H) , 2.70 (s, 3H) .
To a mixture of 6-chloro-2-methyl-3-nitropyridin-4-amine (IV-4, 10.0 g, 53.3 mmol) , zinc dust (0.87 g, 13.3 mmol) and zinc cyanide (7.52 g, 63.9 mmol) in dimethylacetamide (100 mL) were added tris (dibenzylideneacetone) dipalladium (4.88 g, 5.33 mmol) and 1, 1'-bis (diphenylphosphino) ferrocene (2.96 g, 5.33 mmol) . The reaction mixture was degassed and backfilled with nitrogen three times, and stirred at 120 ℃ under N
2 atmosphere overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (200 mL) , washed with brine (60 mL x 4) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 4-amino-6-methyl-5-nitropicolinonitrile (IV-5, 6.00 g, 63%) as a yellow solid. LC-MS (ESI) : m/z 179.2 [M+H]
+.
To a solution of 4-amino-6-methyl-5-nitropicolinonitrile (IV-5, 6.00 g, 33.6 mmol) in methanol (60 mL) was added concentrated sulfuric acid (30 mL) dropwise at 0 ℃. The mixture was heated to 70 ℃ and stirred overnight. The reaction mixture was poured into ice water (50 mL) , adjusted to pH 10 with saturated aq. Na
2CO
3 and extracted with ethyl acetate (100 mL x 3) . The combined organic layers were washed with brine (100 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford methyl 4-amino-6-methyl-5-nitropicolinate (IV-6, 4.60 g, 65%) as a yellow solid. LC-MS (ESI) : m/z 212.2 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.47 (s, 1H) , 7.43 (s, 2H) , 3.84 (s, 3H) , 2.49 (s, 3H) .
To a solution of methyl 4-amino-6-methyl-5-nitropicolinate (IV-6, 4.60 g, 21.7 mmol) in tetrahydrofuran (25 mL) and dichloromethane (25 mL) was added diisobutyl aluminium hydride (43.6 mL, 43.5 mmol, 1 M in hexane) dropwise at 0 ℃. The resulting mixture was warmed to room temperature and stirred for 2 hrs. The reaction mixture was quenched with saturated aq. NH
4Cl (100 mL) at 0 ℃ and extracted with ethyl acetate (100 mL x 3) . The combined organic layers were washed with brine (100 mL x 2) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford (4-amino-6-methyl-5-nitropyridin-2-yl) methanol (IV-7, 3.60 g, 90%) as a yellow solid. LC-MS (ESI) : m/z 184.2 [M+H]
+.
To a solution of (4-amino-6-methyl-5-nitropyridin-2-yl) methanol (IV-7, 3.60 g, 19.6 mmol) in tetrahydrofuran (40 mL) was added phosphorus tribromide (11.7 g, 43.2 mmol) dropwise at 0 ℃. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with water (50 mL) at 0 ℃ and extracted with ethyl acetate (80 mL x 3) . The combined organic layers were washed with brine (180 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 6- (bromomethyl) -2-methyl-3-nitropyridin-4-amine (IV-8, 2.20 g, 46%) as a yellow solid. LC-MS (ESI) : m/z 246.1 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.50 (s, 2H) , 7.07 (s, 1H) , 4.62 (s, 2H) , 2.61 (s, 3H) .
To a solution of 6- (bromomethyl) -2-methyl-3-nitropyridin-4-amine (IV-8, 2.20 g, 8.94 mmol) in methanol (20 mL) was added sodium methoxide (3.30 mL, 17.8 mmol, 5.4 M in methanol) dropwise at 0 ℃. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with water (50 mL) at 0 ℃ and extracted with ethyl acetate (100 mL x 3) . The combined organic layers were washed with brine (150 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 6- (methoxymethyl) -2-methyl-3-nitropyridin-4-amine (IV-9, 700 mg, 40%) as a yellow solid. LC-MS (ESI) : m/z 198.2 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 6.70 (s, 1H) , 5.93 (s, 2H) , 4.42 (s, 2H) , 3.48 (s, 3H) , 2.70 (s, 3H) .
To a solution of 6- (methoxymethyl) -2-methyl-3-nitropyridin-4-amine (IV-9, 700 mg, 3.55 mmol) in methanol (10 mL) was added palladium (10%on carbon, 70.0 mg) . The reaction mixture was degassed and backfilled with H
2 three times, and stirred at room temperature under H
2 atmosphere (1 atm) overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford N-methoxy-N-methyl-3-oxocyclopentane-1-carboxamide (IV-10, 570 mg, 96%) as a white solid. LC-MS (ESI) : m/z 168.3 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 6.61 (s, 1H) , 4.38 (s, 2H) , 3.42 (s, 3H) , 2.41 (s, 3H) .
To a mixture of 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxylic acid (Intermediate D, 6.00 g, 20.3 mmol) , 2- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (11.6 g, 30.5 mmol) and N, O-dimethylhydroxylamine hydrochloride (2.59 g, 26.5 mmol) in N, N-dimethylformamide (60 mL) was added diisopropylethylamine (7.91 g, 61.1 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3) . The combined organic layers were washed with brine (50 mL x 5) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 1- (tert-butyl) -N-methoxy-N-methyl-3- (1, 4- dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxamide (IV-11, 6.50 g, 95%) as a white solid. LC-MS (ESI) : m/z 338.2 [M+H]
+.
To a solution of 1- (tert-butyl) -N-methoxy-N-methyl-3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxamide (IV-11, 5.00 g, 14.8 mmol) in tetrahydrofuran (50 mL) and dichloromethane (50 mL) was added dropwise diisobutyl aluminium hydride (29.7 mL, 29.6 mmol, 1 M in hexane) at 0 ℃. The mixture was warmed to room temperature and stirred for 2 hrs. The reaction mixture was quenched with saturated aq. NH
4Cl (150 mL) at 0 ℃ and extracted with ethyl acetate (200 mL x 3) . The combined organic layers were washed with brine (300 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carbaldehyde (IV-12, 1.63 g, 40%) as a white solid. LC-MS (ESI) : m/z 279.1 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 9.87 (s, 1H) , 6.77 (s, 1H) , 3.99 -3.87 (m, 4H) , 3.64 -3.51 (m, 1H) , 2.32 -2.63 (m, 1H) , 2.18 -2.05 (m, 2H) , 1.94 -1.76 (m, 3H) , 1.69 (s, 9H) .
To a mixture of 6- (methoxymethyl) -2-methylpyridine-3, 4-diamine (IV-10, 570 mg, 3.41 mmol) and 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carbaldehyde (IV-12, 1.14 g, 4.09 mmol) in acetic acid (20 mL) was added cupric acetate (619 mg, 3.41 mmol) . The mixture was stirred at 50 ℃ for 2 hrs. The reaction mixture was poured into ice water (20 mL) , adjusted to pH 10 with saturated aq. Na
2CO
3 at 0 ℃and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford methyl 2- (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) -6- (methoxymethyl) -4-methyl-3H-imidazo [4, 5-c] pyridine (IV-13, 680 mg, 47%) as a white solid. LC-MS (ESI) : m/z 426.2 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 10.07 (s, 1H) , 7.39 (s, 1H) , 7.04 (s, 1H) , 4.66 (s, 2H) , 3.98 -3.88 (m, 4H) , 3.50 (s, 3H) , 2.88 (s, 3H) , 2.34 -2.28 (m, 1H) , 2.22 -2.11 (m, 2H) , 2.01 -1.84 (m, 4H) , 1.70 (s, 9H) .
To a solution of 2- (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) -6- (methoxymethyl) -4-methyl-3H-imidazo [4, 5-c] pyridine (IV-13, 680 mg, 1.60 mmol) in acetone (7 mL) and water (7 mL) was added p-toluenesulfonic acid monohydrate (138 mg, 0.80 mmol) . The mixture was stirred at 60 ℃ overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 3- (1- (tert-butyl) -5- (6- (methoxymethyl) -4-methyl-3H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-one (IV-14, 570 mg, 94%) as a white solid. LC-MS (ESI) : m/z 382.2 [M+H]
+.
To a mixture of methyl 3- (1- (tert-butyl) -5- (6- (methoxymethyl) -4-methyl-3H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-one (IV-14, 570 mg, 1.49 mmol) and triethylamine (303 mg, 2.98 mmol) in dichloromethane (6 mL) was added (2- (chloromethoxy) ethyl) trimethylsilane (299 mg, 1.79 mmol) dropwise at 0 ℃. The resulting mixture was warmed to room temperature and stirred for 3 hrs. The reaction mixture was quenched with water (15 mL) and extracted with dichloromethane (15 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 3- (1- (tert-butyl) -5- (6- (methoxymethyl) -4-methyl-3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-one (IV-15, 560 mg, 73%) as a white solid. LC-MS (ESI) : m/z 512.3 [M+H]
+.
To a solution of 3- (1- (tert-butyl) -5- (6- (methoxymethyl) -4-methyl-3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-one (IV-15, 560 mg, 1.09 mmol) in tetrahydrofuran (5 mL) was added L-selectride (2.20 mL, 2.19 mmol, 1 M in tetrahydrofuran) at -60 ℃ under nitrogen atmosphere. The mixture was stirred at -60 ℃ for 1.5 hrs. The reaction mixture was quenched with saturated aq. NH
4Cl (20 mL) at 0 ℃ and extracted with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (1- (tert-butyl) -5- (6- (methoxymethyl) -4-methyl-3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-ol (IV-16, 466 mg, 83%) as a white solid. LC-MS (ESI) : m/z 514.3 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 7.46 (s, 1H) , 7.12 (s, 1H) , 6.18 (s, 2H) , 4.68 (s, 2H) , 4.51 -4.38 (m, 1H) , 3.57 -3.45 (m, 6H) , 2.90 (s, 3H) , 2.58 -2.46 (m, 1H) , 2.17 -2.02 (m, 2H) , 1.95 -1.87 (m, 2H) , 1.82 -1.74 (m, 2H) , 1.71 (s, 9H) , 0.84 (t, J = 8.0 Hz, 2H) , -0.11 --0.16 (m, 9H) .
To a mixture of cis-3- (1- (tert-butyl) -5- (6- (methoxymethyl) -4-methyl-3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-ol (IV-16, 530 mg, 1.03 mmol) and pyridine (245 mg, 3.095 mmol) in dichloromethane (6 mL) was added 4-nitrophenyl carbonochloridate (416 mg, 2.06 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred for 2 hrs. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (1- (tert-butyl) -5- (6- (methoxymethyl) -4-methyl-3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (IV-17, 510 mg, 73%) as a white solid. LC-MS (ESI) : m/z 679.4 [M+H]
+.
To a solution of cis-3- (1- (tert-butyl) -5- (6- (methoxymethyl) -4-methyl-3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (IV-17, 510 mg, 0.75 mmol) in tetrahydrofuran (6 mL) were added isopropylamine (58.0 mg, 0.977 mmol) and diisopropylethylamine (486 mg, 3.75 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred for 2 hrs. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (1- (tert-butyl) -5- (6- (methoxymethyl) -4-methyl-3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (IV-18, 430 mg, 96%) as a white solid. LC-MS (ESI) : m/z 599.4 [M+H]
+.
cis-3- (1- (tert-butyl) -5- (6- (methoxymethyl) -4-methyl-3- ( (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (IV-18, 430 mg, 0.72 mmol) was separated by chiral SFC to afford two enantiomers, both as a white solid.
Enantiomer 1 (IV-19a, 100%ee) : Retention time: 1.594 min. LC-MS (ESI) : m/z 599.4 [M+H]
+.
Enantiomer 2 (IV-19b, 98.5%ee) : Retention time: 1.868 min. LC-MS (ESI) : m/z 599.4 [M+H]
+.
Analytical method: Column: (R, R) -Whelk-O1, 100×4.6 mm I.D., 5 um; Mobile phase: A for CO
2 and B for IPA (0.05%DEA) ; Gradient: 8 min @B 40%; Flow rate: 2.5 mL/min; Back pressure: 100 bar; Column temperature: 40 ℃.
SFC Method: Instrument: Waters Thar 80 preparative SFC; Column: (R, R) WHELK, 250×21.2 mm I.D., 5 μm; Mobile phase: A for CO
2 and B for IPA + 0.1%NH
3·H
2O; Gradient: B 35%; Flow rate: 40 mL/min; Back pressure: 100 bar; Column temperature: 35 ℃; Wavelength: 220 nm; Cycle-time: 10 mins.
To a solution of enantiomer 1 (IV-19a, 120 mg, 0.20 mmol) in trifluoroacetic acid (2 mL) was added methoxybenzene (65.0 mg, 0.600 mmol) . The mixture was stirred at 50 ℃ for 30 hrs. The reaction mixture was quenched with saturated aq. NaHCO
3 (10 mL) at 0 ℃, and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (3- (6- (methoxymethyl) -4-methyl-1H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (IV, 38.0 mg, 46%, 99.4%ee) as a white solid. LC-MS (ESI) : m/z 413.3 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) (tautomer ratio ~ 4: 1) δ 13.17 & 13.11 (s, 1H) , 12.94 (s, 1H) , 7.37 & 7.26 (s, 1H) , 6.98 (d, J = 8.0 Hz, 1H) , 6.73 & 6.70 (s, 1H) , 5.10 -4.96 (m, 1H) , 4.51 (s, 2H) , 3.62 -3.52 (m, 1H) , 3.37 & 3.36 (s, 3H) , 3.24 -3.16 (m, 1H) , 2.70 & 2.68 (s, 3H) , 2.18 -1.65 (m, 6H) , 1.04 (d, J = 6.4 Hz, 6H) .
Retention time: 3.354 min.
SFC method: Column: ChiralCel OZ, 100×4.6 mm I.D., 5 μm; Mobile phase: A for CO
2 and B for methanol (0.05%DEA) ; Gradient: 8 min @30%B; Flow rate: 2.5 mL/min; Column temperature: 40 ℃.
To a solution of enantiomer 2 (IV-19b, 100 mg, 0.16 mmol) in trifluoroacetic acid (2 mL) was added methoxybenzene (54.0 mg, 0.50 mmol) . The mixture was stirred at 50 ℃ for 30 hrs. The reaction mixture was quenched with saturated aq. NaHCO
3 (10 mL) at 0 ℃ and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (3- (6- (methoxymethyl) -4-methyl-1H-imidazo [4, 5-c] pyridin-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (V, 41.0 mg, 60%, 94.2%ee) as a yellow solid. LC-MS (ESI) : m/z 413.3 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) (tautomer ratio ~ 4: 1) δ 13.17 & 13.11 (s, 1H) , 12.94 (s, 1H) , 7.37 & 7.26 (s, 1H) , 6.98 (d, J = 6.4 Hz, 1H) , 6.73 & 6.70 (s, 1H) , 5.11 -4.96 (m, 1H) , 4.51 (s, 2H) , 3.62 -3.52 (m, 1H) , 3.37 & 3.36 (s, 3H) , 3.24 -3.16 (m, 1H) , 2.70 & 2.68 (s, 3H) , 2.18 -1.65 (m, 6H) , 1.04 (d, J = 6.4 Hz, 6H) .
Retention time: 2.698 min.
SFC method: Column: ChiralCel OZ, 100×4.6 mm I.D., 5 μm; Mobile phase: A for CO
2 and B for methanol (0.05%DEA) ; Gradient: 8 min @30%B; Flow rate: 2.5 mL/min; Column temperature: 40 ℃.
Synthesis of cis-3- (3- (4-methyl-1H-benzo [d] imidazol-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (VI) and cis-3- (3- (4-methyl-1H-benzo [d] imidazol-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (VII)
To a mixture of 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxylic acid (Intermediate D, 1.00 g, 3.39 mmol) and 3-methylbenzene-1, 2-diamine (VI-1, 0.42 g, 3.39 mmol) in dichloromethane (10 mL) were added propylphosphonic anhydride (2.60 g, 4.07 mmol, 50%w. t. in ethyl acetate) and diisopropylethylamine (2.80 mL, 16.9 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (30 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford N- (2-amino-3-methylphenyl) -1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxamide (VI-2, 1.01 g, 75%) as a white solid. LC-MS (ESI) : m/z 399 [M+H]
+.
A solution of N- (2-amino-3-methylphenyl) -1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxamide (VI-2, 1.01 g, 2.53 mmol) in acetic acid (10 mL) was heated to 40 ℃ and stirred for 5 hrs. The reaction mixture was quenched with saturated aq. NaHCO
3 (50 mL) at 0 ℃ and extracted with ethyl acetate (40 mL x 3) . The combined organic layers were washed with brine (40 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 2- (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) -7-methyl-1H-benzo [d] imidazole (VI-3, 900 mg , 93%) as a white solid. LC-MS (ESI) : m/z 381 [M+H]
+.
To a mixture of 2- (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) -7-methyl-1H-benzo [d] imidazole (VI-3, 900 mg, 2.36 mmol) and triethylamine (478 mg, 4.73 mmol) in dichloromethane (10 mL) was added (2- (Chloromethoxy) ethyl) trimethylsilane (473 mg, 2.83 mmol) dropwise at 0 ℃. The mixture was warmed to room temperature and stirred for 3 hrs. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 2- (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole (VI-4, 1.20 g, 99 %) as a white solid. LC-MS (ESI) : m/z 511 [M+H]
+.
To a solution of 2- (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole (VI-4, 1.20 g, 2.35 mmol) in acetone (6 mL) and water (6 mL) was added p-toluenesulfonic acid (0.22 g, 1.17 mmol) . The mixture was stirred at 60 ℃ for 15 hrs. The reaction mixture was diluted water (20 mL) and extracted with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 3- (1- (tert-butyl) -5- (7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-one (VI-5, 570 mg, 52%) as a white solid. LC-MS (ESI) : m/z 467 [M+H]
+.
To a solution of 3- (1- (tert-butyl) -5- (7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-one (VI-5, 470 mg, 1.00 mmol) in tetrahydrofuran (5 mL) was added L-selectride (2 mL, 2.01 mmol, 1 M in tetrahydrofuran) dropwise at -60 ℃ under nitrogen atmosphere. The mixture was stirred at -60 ℃ for 1.5 hrs. The reaction mixture was quenched with saturated aq. NH
4Cl (20 mL) at 0 ℃ and extracted with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (1- (tert-butyl) -5- (7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-ol (VI-6, 375 mg, 80%) as a white solid. LC-MS (ESI) : m/z 469 [M+H]
+.
To a mixture of cis-3- (1- (tert-butyl) -5- (7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-ol (VI-6, 460 mg, 0.98 mmol) and pyridine (233 mg, 2.94 mmol) in dichloromethane (5 mL) was added 4-nitrophenyl carbonochloridate (396 mg, 1.96 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred for 2 hrs. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (1- (tert-butyl) -5- (7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (VI-7, 450 mg, 73%) as a white solid. LC-MS (ESI) : m/z 634 [M+H]
+.
To a solution of cis-3- (1- (tert-butyl) -5- (7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (VI-7, 450 mg, 0.71 mmol) in tetrahydrofuran (7 mL) were added isopropylamine (55.0 mg, 0.92 mmol) and diisopropylethylamine (459 mg, 3.55 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred for 2 hrs. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (1- (tert-butyl) -5- (7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (VI-8, 330 mg, 85%) as a white solid. LC-MS (ESI) : m/z 554 [M+H]
+.
cis-3- (1- (tert-butyl) -5- (7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (VI-8, 330 mg, 0.59 mmol) was separated by chiral SFC to afford two enantiomers.
Enantiomer 1 (VI-9a, 100%ee) : Retention time: 1.197 min. LC-MS (ESI) : m/z 554 [M+H]
+.
Enantiomer 2 (VI-9b, 100%ee) : Retention time: 1.462 min. LC-MS (ESI) : m/z 554 [M+H]
+.
Analytical method: Column: ChiralPak AD, 150×4.6 mm I.D., 3 μm; Mobile phase: A for CO
2 and B for Isopropanol (0.05%DEA) ; Gradient: B 25%; Flow rate: 2.4 mL/min; Back pressure: 100 bar; Column temperature: 35 ℃; Wavelength: 220 nm.
SFC Method: Instrument: MG Ⅱ preparative SFC (SFC-1) ; Column: ChiralPak AD, 250×30 mm I.D., 10 μm; Mobile phase: A for CO
2 and B for Isopropanol (0.1%NH
3·H
2O) ; Gradient: B 20%; Flow rate: 60 mL /min; Back pressure: 100 bar; Column temperature: 38℃; Wavelength: 220 nm; Cycle time: ~4 mins.
To a solution of enantiomer 1 (VI-9a, 75.0 mg, 0.13 mmol) in trifluoroacetic acid (2 mL) was added methoxybenzene (44.0 mg, 0.40 mmol) . The mixture was stirred 50 ℃for 10 hrs. The reaction mixture was quenched with saturated aq. NaHCO
3 (10 mL) at 0 ℃ and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (3- (4-methyl-1H-benzo [d] imidazol-2-yl) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate (VI, 41.0 mg, 82%, 100%ee) as a white solid. LC-MS (ESI) : m/z 368 [M+H]
+.
1HNMR (400 MHz, DMSO-d
6) (the ratio of tautomers ~1: 1) δ 12.99 (s, 1H) , 12.60 & 12.56 (s, 1H) , 7.41 -7.23 (m, 1H) , 7.08 -6.92 (m, 3H) , 6.67 (s, 1H) , 5.07 -5.00 (m, 1H) , 3.63 -3.54 (m, 1H) , 3.22 -3.17 (m, 1H) , 2.54 & 2.53 (s, 3H) , 2.17 -2.06 (m, 1H) , 1.98 -1.65 (m, 5H) , 1.04 (d, J = 6.4 Hz, 6H) .
Retention time: 1.472 min.
SFC Method: Column: ChiralPak AY, 100×4.6 mm I.D., 5 μm; Mobile phase: A for CO
2 and B for methanol (0.05%DEA) ; Gradient: 8 min @30%B; Flow rate: 2.5 mL/min; Column temperature: 40 ℃.
To a solution of enantiomer 2 (VI-9b, 65.0 mg, 0.11 mmol) in trifluoroacetic acid (2 mL) was added methoxybenzene (38.0 mg, 0.35 mmol) . The mixture was stirred at 50 ℃ for 10 hrs. The reaction mixture was quenched with saturated aq. NaHCO
3 (10 mL) at 0 ℃ and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (3- (4-methyl-1H-benzo [d] imidazol-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (VII, 35.0 mg, 80%, 100%ee) as a white solid. LC-MS (ESI) : m/z 368 [M+H]
+.
1HNMR (400 MHz, DMSO-d
6) (the ratio of tautomers ~1: 1) δ 12.99 (s, 1H) , 12.60 & 12.56 (s, 1H) , 7.42 -7.23 (m, 1H) , 7.08 -6.91 (m, 3H) , 6.67 (s, 1H) , 5.06 -5.00 (m, 1H) , 3.64 -3.52 (m, 1H) , 3.21 -3.16 (m, 1H) , 2.54 & 2.53 (s, 3H) , 2.18 -2.05 (m, 1H) , 1.98 -1.65 (m, 5H) , 1.04 (d, J = 6.0 Hz, 6H) .
Retention time: 3.986 min.
SFC Method: Column: ChiralPak AY, 100×4.6 mm I.D., 5 μm; Mobile phase: A for CO
2 and B for methanol (0.05%DEA) ; Gradient: 8 min @30%B; Flow rate: 2.5 mL/min; Column temperature: 40 ℃.
Synthesis of cis-3- (3- (6- (methoxymethyl) -4-methyl-1H-benzo [d] imidazol-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (VIII) & cis-3- (3- (6- (methoxymethyl) -4-methyl-1H-benzo [d] imidazol-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (IX)
To a solution of 4-bromo-2-methyl-6-nitroaniline (VIII-1, 25.0 g, 108 mmol) and zinc cyanide (19.0 g, 162 mmol) in N, N-dimethylformamide (250 mL) were added tris (dibenzylideneacetone) dipalladium (4.95 g, 5.41 mmol) and 1, 1'-bis (diphenylphosphino) ferrocene (6.00 g, 10.8 mmol) . The reaction mixture was degassed and backfilled with nitrogen three times and stirred at 120 ℃ under N
2 atmosphere for 15 hrs. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (500 mL) and washed with brine (150 mL x 5) . The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 4-amino-3-methyl-5-nitrobenzonitrile (VIII-2, 9.20 g, 48%) as a yellow solid. LC-MS (ESI) : m/z 178.1 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.35 (s, 1H) , 7.75 (s, 2H) , 7.67 (s, 1H) , 2.22 (s, 3H) .
To a solution of 4-amino-3-methyl-5-nitrobenzonitrile (VIII-2, 9.20 g, 51.9 mmol) in methanol (90 mL) was added concentrated sulfuric acid (20 mL) dropwise at 0 ℃. The resulting mixture was warmed to 70 ℃ and stirred overnight. The reaction mixture was cooled to room temperature, poured into ice water and adjusted to pH 10 with saturated aq. sodium carbonate at 0 ℃. The aqueous layer was extracted with ethyl acetate (200 mL x 3) . The combined organic layers were washed with brine (200 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford methyl 4-amino-3-methyl-5-nitrobenzoate (VIII-3, 8.50 g, 78%) as a yellow solid. LC-MS (ESI) : m/z 211.1 [M+H]
+.
To a solution of methyl 4-amino-3-methyl-5-nitrobenzoate (VIII-3, 8.50 g, 40.4 mmol) in tetrahydrofuran (85 mL) and dichloromethane (85 mL) was added diisobutyl aluminium hydride (81 mL, 80.8 mmol, 1 M in hexane) dropwise at 0 ℃. The resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was quenched with saturated aq. NH
4Cl (150 mL) at 0 ℃ and extracted with ethyl acetate (200 mL x 3) . The combined organic layers were washed with brine (200 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford (4-amino-3-methyl-5-nitrophenyl) methanol (VIII-4, 5.20 g, 70%) as a yellow solid. LC-MS (ESI) : m/z 183.2 [M+H]
+.
To a solution of (4-amino-3-methyl-5-nitrophenyl) methanol (VIII-4, 3.70 g, 20.3 mmol) in methanol (80 mL) was added concentrated sulfuric acid (20 mL) dropwise at 0 ℃. The reaction mixture was warmed to 50 ℃ and stirred for 1 hr. The mixture was cooled to room temperature, poured into ice water, adjusted to pH 10 with saturated aq. Na
2CO
3 at 0 ℃ and extracted with ethyl acetate (100 mL x 3) . The combined organic layers were washed with brine (100 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 4- (methoxymethyl) -2-methyl-6-nitroaniline (VIII- 5, 2.60 g, 65%) as a yellow solid. LC-MS (ESI) : m/z 197.2 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.82 (s, 1H) , 7.31 (s, 1H) , 7.16 (s, 2H) , 4.27 (s, 2H) , 3.24 (s, 3H) , 2.21 (s, 3H) .
To a solution of 4- (methoxymethyl) -2-methyl-6-nitroaniline (VIII-5, 2.80 g, 14.2 mmol) in ethyl alcohol (48 mL) and water (8 mL) were added iron dust (4.30 g, 77.0 mmol) and ammonium chloride (6.11 g, 114 mmol) . The resulting mixture was stirred at 70 ℃ for 2 hrs. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl alcohol (30 mL) and the filtrate was concentrated under reduced pressure to give a residue. To the residue was added water (30 mL) and the pH was adjusted to 10 with saturated aq. Na
2CO
3 and then the mixture was extracted with ethyl acetate (100 mL x 3) . The combined organic layers were washed with brine (40 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography to afford 5- (methoxymethyl) -3-methylbenzene-1, 2-diamine (VIII-6, 1.37 g, 58%) as a yellow solid. LC-MS (ESI) : m/z 167.2 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 6.40 (d, J = 1.6 Hz, 1H) , 6.28 (d, J = 1.2 Hz, 1H) , 4.29 (s, 4H) , 4.12 (s, 2H) , 3.17 (s, 3H) , 2.04 (s, 3H) .
To a mixture of 4- (methoxymethyl) -2-methyl-6-nitroaniline (VIII-6, 0.68 g, 4.07 mmol) and 1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxylic acid (Intermediate D, 1.20 g, 4.07 mmol) in dichloromethane (10 mL) were added propylphosphonic anhydride (3.12 g, 4.89 mmol, 50%w. t. in ethyl acetate) and diisopropylethylamine (2.63 g, 20.3 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford N- (2-amino-5- (methoxymethyl) -3-methylphenyl) -1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxamide (VIII-7, 1.10 g, 61%) as a white solid. LC-MS (ESI) : m/z 443.2 [M+H]
+.
A solution of N- (2-amino-5- (methoxymethyl) -3-methylphenyl) -1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazole-5-carboxamide (VIII-7, 800 mg, 1.80 mmol) in acetic acid (8 mL) was heated to 40 ℃ and stirred for 5 hrs. The reaction mixture was quenched with saturated aq. NaHCO
3 (50 mL) at 0 ℃ and extracted with ethyl acetate (30 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2- (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) -5- (methoxymethyl) -7-methyl-1H-benzo [d] imidazole (VIII-8, 310 mg, 40%) as a white solid. LC-MS (ESI) : m/z 425.3 [M+H]
+.
To a solution of 2- (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) -5- (methoxymethyl) -7-methyl-1H-benzo [d] imidazole (VIII-8, 430 mg, 1.01 mmol) and triethylamine (205 mg, 2.02 mmol) in dichloromethane (5 mL) was added (2- (chloromethoxy) ethyl) trimethylsilane (202 mg, 1.21 mmol) dropwise at 0 ℃. The mixture was warmed to room temperature and stirred for 3 hrs. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (15 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 2- (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) -5- (methoxymethyl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole (VIII-9, 550 mg, 98%) as a white solid. LC-MS (ESI) : m/z 555.3 [M+H]
+.
To a solution of 2- (1- (tert-butyl) -3- (1, 4-dioxaspiro [4.4] nonan-7-yl) -1H-pyrazol-5-yl) -5- (methoxymethyl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole (VIII-9, 550 mg, 0.99 mmol) in acetone (5 mL) and water (5 mL) was added p-toluenesulfonic acid monohydrate (94.2 mg, 0.49 mmol) . The mixture was stirred at 60 ℃ for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford 3- (1- (tert-butyl) -5- (5- (methoxymethyl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-one (VIII-10, 350 mg, 69%) as a white solid. LC-MS (ESI) : m/z 511.3 [M+H]
+.
To a solution of 3- (1- (tert-butyl) -5- (5- (methoxymethyl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-one (VIII-10, 350 mg, 0.68 mmol) in tetrahydrofuran (5 mL) was added L-selectride (1.37 mL, 1.37 mmol, 1 M in tetrahydrofuran) at -60 ℃ under nitrogen atmosphere. The mixture was stirred at -60 ℃ for 1.5 hrs. The reaction mixture was quenched with saturated aq. NH
4Cl (20 mL) at 0 ℃ and extracted with ethyl acetate (20 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (1- (tert-butyl) -5- (5- (methoxymethyl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-ol (VIII-11, 284 mg, 81%) as a white solid. LC-MS (ESI) : m/z 513.3 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.57 (s, 1H) , 7.38 (s, 1H) , 7.26 (s, 1H) , 6.43 -6.34 (m, 2H) , 4.74 (s, 2H) , 4.65 -4.56 (m, 1H) , 3.74 (t, J = 8.0 Hz, 2H) , 3.61 (s, 3H) , 3.52 -3.42 (m, 1H) , 2.88 (s, 3H) , 2.75 -2.63 (m, 1H) , 2.32 -2.19 (m, 3H) , 2.11 -2.01 (m, 3H) , 1.88 (s, 9H) , 1.03 (t, J = 8.0 Hz, 2H) , 0.05 (s, 9H) .
To a mixture of cis-3- (1- (tert-butyl) -5- (5- (methoxymethyl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentan-1-ol (VIII-11, 340 mg, 0.66 mmol) and pyridine (157 mg, 1.99 mmol) in dichloromethane (5 mL) was added 4-nitrophenyl carbonochloridate (267 mg, 1.32 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred for 2 hrs. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (1- (tert-butyl) -5- (5- (methoxymethyl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate (VIII-12, 210 mg, 47%) as a white solid. LC-MS (ESI) : m/z 678.3 [M+H]
+.
To a solution of cis-3- (1- (tert-butyl) -5- (5- (methoxymethyl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (VIII-12, 210 mg, 0.31 mmol) in tetrahydrofuran (5 mL) were added isopropylamine (24 mg, 0.40 mmol) and diisopropylethylamine (200 mg, 1.55 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred for 2 hrs. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (1- (tert-butyl) -5- (5- (methoxymethyl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (VIII-13, 180 mg, 97%) as a white solid. LC-MS (ESI) : m/z 598.4 [M+H]
+.
cis-3- (1- (tert-butyl) -5- (5- (methoxymethyl) -7-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (VIII-13, 180 mg, 0.30 mmol) was separated by chiral SFC to afford two enantiomers:
Enantiomer 1 (VIII-14a, 100%ee) : Retention time: 3.121 min. LC-MS (ESI) : m/z 598.4 [M+H]
+.
Enantiomer 2 (VIII-14b, 100%ee) : Retention time: 4.185 min; LC-MS (ESI) : m/z 598.4 [M+H]
+.
Analytical method: Column: ChiralPak AD, 250×4.6 mm I.D., 5 um; Mobile phase: A for CO
2 and B for IPA (0.05%DEA) ; Gradient: 8 min @B 20%; Flow rate: 2.0 mL/min; Back pressure: 100 bar; Column temperature: 35 ℃.
SFC Method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralPak AD, 250×21.2 mm I.D., 5 μm; Mobile phase: A for CO
2 and B for IPA + 0.1%NH
3·H
2O; Gradient: B 12%; Flow rate: 40mL /min; Back pressure: 100 bar; Column temperature: 35 ℃; Wavelength: 297 nm; Cycle-time: 8 mins.
To a solution of enantiomer 1 (VIII-14a, 65.0 mg, 0.11 mmol) in trifluoroacetic acid (2 mL) was added methoxybenzene (36.0 mg, 0.32 mmol) . The mixture was stirred at 50 ℃ for 6 hrs. The reaction mixture was quenched with saturated aq. NaHCO
3 (10 mL) at 0 ℃ and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (3- (6- (methoxymethyl) -4-methyl-1H-benzo [d] imidazol-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (VIII, 18.0 mg, 40%, 94%ee) as a white solid. LC-MS (ESI) : m/z 412.3 [M+H]
+.
1HNMR (400 MHz, DMSO-d
6) (tautomer ratio ~ 2: 1) δ 12.99 (s, 1H) , 12.61 & 12.57 (s, 1H) , 7.36 & 7.20 (s, 1H) , 7.06 -6.84 (m, 2H) , 6.66 (s, 1H) , 5.09 -4.98 (m, 1H) , 4.45 (s, 2H) , 3.65 -3.52 (m, 1H) , 3.28 (s, 3H) , 3.21 -3.12 (m, 1H) , 2.53 (s, 3H) , 2.21 -1.58 (m, 6H) , 1.04 (d, J = 6.0 Hz, 6H) .
Retention time: 5.182 min.
SFC Method: Column: ChiralCel OX, 100×4.6 mm I.D., 5 μm; Mobile phase: A for CO
2 and B for methanol (0.05%DEA) ; Gradient: 8 min @20%B; Flow rate: 2.5 mL/min; Column temperature: 40 ℃.
To a solution of enantiomer 2 (VIII-14b, 70.0 mg, 0.11 mmol) in trifluoroacetic acid (2 mL) was added methoxybenzene (38.4 mg, 0.35 mmol) . The mixture was stirred at 50 ℃ for 6 hrs. The reaction mixture was quenched with saturated aq. NaHCO
3 (10 mL) at 0 ℃ and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography to afford cis-3- (3- (6- (methoxymethyl) -4-methyl-1H-benzo [d] imidazol-2-yl) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate (IX, 18.0 mg, 37%, 100%ee) as a yellow solid.
LC-MS (ESI) : m/z 412.3 [M+H]
+.
1HNMR (400 MHz, DMSO-d
6) (tautomer ratio ~ 2: 1) δ 12.99 (s, 1H) , 12.61 & 12.56 (s, 1H) , 7.33 & 7.20 (s, 1H) , 7.06 -6.84 (m, 2H) , 6.66 (s, 1H) , 5.10 -4.98 (m, 1H) , 4.45 (s, 2H) , 3.65 -3.52 (m, 1H) , 3.28 (s, 3H) , 3.21 -3.12 (m, 1H) , 2.53 (s, 3H) , 2.21 -1.58 (m, 6H) , 1.04 (d, J = 6.0 Hz, 6H) .
Retention time: 6.432 min.
SFC Method: Column: ChiralCel OX, 100×4.6 mm I.D., 5 μm; Mobile phase: A for CO
2 and B for methanol (0.05%DEA) ; Gradient: 8 min @20%B; Flow rate: 2.5 mL/min; Column temperature: 40 ℃.
Biological Example 1. Measurement of Kinase Inhibitory Activity
Compounds of the present disclosure are expected to be CDK2 inhibitors. The IC50 values of compounds of the present disclosure against various CDKs can be measured by using the experimental procedures described below, which have been used for testing other CDK2 inhibitors.
CDK2/CyclinE1 kinase inhibitory activity (IC50) : 5 μl of various dilutions of test compound in 1x kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Brij-35) was mixed with 10 μL of CDK2/CyclinE1 (Carna, 04-165#, final concentration 3 nM in 1 × Kinase buffer) in 384 plates and incubated at room temperature for 10 min. To initiate each reaction, 10 μL of peptide solution containing fluorescently-labeled-peptide18 (5-FAM-QSPKKG-CONH2) (GL, 114202#, final concentration 3000 nM) and ATP (final concentration 77μM) in 1 × Kinase buffer was added to each of the wells containing test compound and CDK2/CyclinE1 mixture. The reaction is then allowed to proceed at 28℃ for 30min and terminated by the addition of 25 μL stop buffer (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2%Coating Reagent #3 (Perkin Elmer, 760050#) and 0.015%Brij-35) .
Following the kinase reaction, Caliper EZ reader II (Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI) was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide 18 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II. These conversion values were then transformed into %inhibition of kinase activity using the formula: %Inhibition = [ (MA –X) / (MA -MI) ] ×100%where MA = conversion value of DMSO only controls, MI = conversion value of no enzyme controls and X = conversion value at any given compound dose. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
CDK1/CyclinB kinase inhibitory activity (IC50) : 5 μl of various dilutions of test compound in 1x kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Brij-35) was mixed with 10 μL of CDK1/CyclinB (Millipore, 14-450M#, final concentration 3 nM in 1 × Kinase buffer) in 384 plates and incubated at room temperature for 10 min. To initiate each reaction, 10 μL of peptide solution containing fluorescently-labeled -peptide18 (5-FAM-QSPKKG-CONH2) (GL, 114202#, final concentration 3000 nM) and ATP (final concentration 20μM) in 1 × Kinase buffer was added to each of the wells containing test compound and CDK1/CyclinB mixture. The reaction is then allowed to proceed at 28℃ for 30min and terminated by the addition of 25 μL stop buffer (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2%Coating Reagent #3 (Perkin Elmer, 760050#) and 0.015%Brij-35) .
Following the kinase reaction, Caliper EZ reader II (Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI) was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide 18 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II. These conversion values were then transformed into %inhibition of kinase activity using the formula: %Inhibition = [ (MA –X) / (MA -MI) ] ×100%where MA = conversion value of DMSO only controls, MI = conversion value of no enzyme controls and X = conversion value at any given compound dose. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
CDK4/CyclinD1 or CDK4/CyclinD3 kinase inhibitory activity (IC50) : 5 μl of various dilutions of test compound in 1x kinase buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Triton X-100 ) was mixed with 10 μL of either CDK4/Cyclin D1 (ProQinase, 0142-0143-1#, final concentration 20nM in 1 x Kinase buffer) or CDK4/CyclinD3 (Carna, 04-105#, final concentration 10nM in 1 × Kinase buffer) in 384 plates and incubated at room temperature for 10 min. To initiate each reaction, 10 μL of peptide solution containing fluorescently-labeled -peptide 8 (5-FAM-IPTSPITTTYFFFKKK-COOH, GL, 112396#, final concentration 3000 nM) and ATP (final concentration 672uM for CDK4/CyclinD1 or 280μM for CDK4/Cyclin D3) in 1 ×Kinase buffer was added to each of the wells containing test compound and CDK4/CyclinD3 mixture. The reaction is then allowed to proceed at 28℃ for 30min and terminated by the addition of 25 μL stop buffer (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2%Coating Reagent #3 (Perkin Elmer, 760050#) and 0.015%Brij-35) .
Following the kinase reaction, Caliper EZ reader II (Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI) was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide 8 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II. These conversion values were then transformed into %inhibition of kinase activity using the formula: %Inhibition = [ (MA –X) / (MA -MI) ] ×100%where MA = conversion value of DMSO only controls, MI = conversion value of no enzyme controls and X = conversion value at any given compound dose. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
CDK6/CyclinD1 or CDK6/CyclinD3 kinase inhibitory activity (IC50) : 5 μl of various dilutions of test compound in 1x kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Brij-35) was mixed with 10 μL of CDK6/CyclinD1 (Carna, 04-114#, final concentration 7.5nM in 1 × Kinase buffer) or CDK6/Cyclin D3 (Carna, 04-107#, final concentration 15nM in 1 × Kinase buffer) in 384 plates and incubated at room temperature for 10 min. To initiate each reaction, 10 μL of peptide solution containing fluorescently-labeled -peptide 8 (5-FAM-IPTSPITTTYFFFKKK-COOH, GL, 112396#, final concentration 3000 nM) and ATP (final concentration 230μM for CDK6/CyclinD1 or 800uM for CDK6/CyclinD3) in 1 × Kinase buffer was added to each of the wells containing test compound and CDK6/CyclinD1 or CDK6/Cyclin D3 mixture. The reaction is then allowed to proceed at 28℃ for 30min and terminated by the addition of 25 μL stop buffer (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2%Coating Reagent #3 (Perkin Elmer, 760050#) and 0.015%Brij-35) .
Following the kinase reaction, Caliper EZ reader II (Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI) was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide 8 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II. These conversion values were then transformed into %inhibition of kinase activity using the formula: %Inhibition = [ (MA –X) / (MA -MI) ] ×100%where MA = conversion value of DMSO only controls, MI = conversion value of no enzyme controls and X = conversion value at any given compound dose. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
CDK7/CyclinH/MAT1 kinase inhibitory activity (IC50) : 5 μl of various dilutions of test compound in 1x kinase buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Triton X-100) was mixed with 10 μL of CDK7/CyclinH/MAT1 (Millipore, 14-476M#, final concentration 12.5nM in 1 × Kinase buffer) in 384 plates and incubated at room temperature for 10 min. To initiate each reaction, 10 μL of peptide solution containing fluorescently-labeled -peptide CTD3 (5-FAM-ACSYSPTSPSYSPTSPSYSPTSPSKK, GL, SY346885#, final concentration 3000 nM) and ATP (final concentration 70μM) in 1 × Kinase buffer was added to each of the wells containing test compound and CDK7/CyclinH/MAT1 mixture. The reaction is then allowed to proceed at 28℃ for 30min and terminated by the addition of 25 μL stop buffer (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2%Coating Reagent #3 (Perkin Elmer, 760050#) and 0.015%Brij-35) .
Following the kinase reaction, Caliper EZ reader II (Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI) was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide CTD3 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II. These conversion values were then transformed into %inhibition of kinase activity using the formula: %Inhibition = [ (MA –X) / (MA -MI) ] ×100%where MA = conversion value of DMSO only controls, MI = conversion value of no enzyme controls and X = conversion value at any given compound dose. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
CDK9/CyclinT1 kinase inhibitory activity (IC50) : 5 μl of various dilutions of test compound in 1x kinase buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01%Triton X-100) was mixed with 10 μL of CDK9/CyclinT1 (Millipore, 14-685M#, final concentration 12.5nM in 1 × Kinase buffer) in 384 plates and incubated at room temperature for 10 min. To initiate each reaction, 10 μL of peptide solution containing fluorescently-labeled -peptide CTD3 (5-FAM-ACSYSPTSPSYSPTSPSYSPTSPSKK, GL, SY346885#, final concentration 3000nM) and ATP (final concentration 10μM) in 1 × Kinase buffer was added to each of the wells containing test compound and CDK9/CyclinT1 mixture. The reaction is then allowed to proceed at 28℃ for 30min and terminated by the addition of 25 μL stop buffer (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2%Coating Reagent #3 (Perkin Elmer, 760050#) and 0.015%Brij-35) .
Following the kinase reaction, Caliper EZ reader II (Downstream voltages: -500V, Upstream voltages: -2250V, Base pressure -0.5 PSI, Screen pressure -1.2 PSI) was used to separate the phosphorylated (product) and the unphosphorylated (substrate) fluorescently-labeled peptide CTD3 based on their different mobility. Both substrate and product were measured and the ratio of these values were used to generate %conversion by Caliper EZ reader II. These conversion values were then transformed into %inhibition of kinase activity using the formula: %Inhibition = [ (MA –X) / (MA -MI) ] ×100%where MA = conversion value of DMSO only controls, MI = conversion value of no enzyme controls and X = conversion value at any given compound dose. IC50 values were then calculated by plotting dose-response curves and then using the XLfit application in Excel software.
Biological activity data for representative compounds of the present disclosure are provided in Table 2 below. Exemplary results are presented as calculated IC
50 values. In Table 2, "A" represents a calculated IC
50 value of less than 10 nM; "B" represents a calculated IC
50 value of greater than or equal to 10 nM and less than 100 nM; "C" represents a calculated IC
50 value of greater than or equal to 100 nM and less than 1 μM; and "D" represents a calculated IC
50 value of 1 μM or greater.
Table 2. Selected in vitro data on different CDKs
The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor (s) , and thus, are not intended to limit the present invention and the appended claims in any way.
The present invention has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.
With respect to aspects of the invention described as a genus, all individual species are individually considered separate aspects of the invention. If aspects of the invention are described as "comprising" a feature, embodiments also are contemplated "consisting of” or "consisting essentially of” the feature.
The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.
The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.
All of the various aspects, embodiments, and options described herein can be combined in any and all variations.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.
Claims (87)
- A compound of Formula I, or a pharmaceutically acceptable salt thereof:wherein:L 1 is a bond, NH, O, optionally substituted C 1-4 alkylene, optionally substituted C 1-4 heteroalkylene, orR 1 is an optionally substituted 5-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl (e.g., 5-or 6-membered heteroaryl, or 8-10 membered bicyclic heteroaryl) ;X is NR 10 or O;Y is a bond, O, NR 10, optionally substituted C 1-4 alkylene, or optionally substituted C 1-4 heteroalkylene;R 2 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or NR 11R 12;wherein:R 10 at each occurrence is independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl;each of R 11 and R 12 is independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl; or a nitrogen protecting group; or R 11 and R 12, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl.
- The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond.
- The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.
- The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted imidazole.
- The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is characterized as having Formula I-1:wherein:R 20 and R 21 are each independently OH, halogen, CN, R g1, OR g1, C (O) R g1, C (O) OR g1, S (O) R g1, S (O) 2R g1, S (O) 2NR aR b, C (O) NR aR b, NR aR b or S (O) (NR c) R g1; or R 20 and R 21, together with the intervening atoms, form an optionally substituted 4-8 membered ring, e.g., an optionally substituted phenyl or optionally substituted 5-or 6-membered heteroaryl;wherein:R a and R b are each independently R g1, C (O) R g1, C (O) OR g1, or C (O) NR g1R g1, or a nitrogen protecting group; or R a and R b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;R c is hydrogen or C 1-4 alkyl; andR g1 at each occurrence is independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 20 and R 21 are each independently hydrogen, OH, halogen, CN, R g2, C (O) R g2, or S (O) 2R g2, wherein R g2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, phenyl, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, or 5-or 6-membered heteroaryl is independently optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , oxo (as valency permits) , OH, CN, C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R s2,wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, andR s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C 1-4 alkoxy optionally substituted with 1-3 F.
- The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 20 and R 21 are each independently hydrogen, halogen, CN, C 1-4 alkyl, C (O) -C 1-4 alkyl, S (O) 2-C 1-4 alkyl, C 1-4 alkyl substituted with 1-3 fluorine, C 1-4 heteroalkyl, C 1-4 heteroalkyl substituted with 1-3 fluorine, phenyl, pyridyl, or pyrazolyl, wherein the phenyl, pyridyl, or pyrazolyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R s2, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C 1-4 alkoxy optionally substituted with 1-3 F.
- The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 20 and R 21 are each independently hydrogen, C 1-4 alkyl, C (O) -C 1-4 alkyl, S (O) 2-C 1-4 alkyl, C 1-4 alkyl substituted with 1-3 fluorine, C 1-4 heteroalkyl, C 1-4 heteroalkyl substituted with 1-3 fluorine, or a group selected from the following:
- The compound of any one of claims 5-8, or a pharmaceutically acceptable salt thereof, wherein R 20 is hydrogen.
- The compound of any one of claims 5-9, or a pharmaceutically acceptable salt thereof, wherein R 21 is hydrogen.
- The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 20 and R 21, together with the intervening atoms, form an optionally substituted phenyl or an optionally substituted 5-or 6-membered heteroaryl.
- The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 20 and R 21, together with the intervening atoms, form a phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R g2, C (O) R g2, or S (O) 2R g2,wherein R g2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, phenyl, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, or 5-or 6-membered heteroaryl is independently optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , oxo (as valency permits) , OH, CN, C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R s2,wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, andR s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C 1-4 alkoxy optionally substituted with 1-3 F.
- The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 20 and R 21, together with the intervening atoms, form a phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, C (O) -C 1-4 alkyl, S (O) 2-C 1-4 alkyl, C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R s2, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C 1-4 alkoxy optionally substituted with 1-3 F.
- The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is NH.
- The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.
- The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, wherein R 1 is pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h1, OR h1, C (O) R h1, C (O) H, C (O) OR h1, COOH, S (O) R h1, S (O) 2R h1, S (O) 2NR aR b, C (O) NR aR b, NR aR b or S (O) (NR c) R h1, wherein R a and R b are each independently hydrogen, R h1, C (O) H, C (O) R h1, C (O) OR h1, CONH 2, C (O) NHR h1, or C (O) NR h1R h1, or a nitrogen protecting group; or R a and R b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;R c is hydrogen or C 1-4 alkyl; andwherein R h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, wherein R 1 is pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h2 or OR h2,wherein R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R s2, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C 1-4 alkoxy optionally substituted with 1-3 F.
- The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:wherein the pyridyl, pyridazinyl, or pyrazinyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h3 or OR h3,wherein R h3 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, or C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5,6-bicyclic or 6, 6-bicyclic heteroaryl having 1-4 ring heteroatoms independently selected from N, O, and S,wherein the 5, 6-bicyclic or 6, 6-bicyclic heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h1, OR h1, C (O) R h1, C (O) H, C (O) OR h1, COOH, S (O) R h1, S (O) 2R h1, S (O) 2NR aR b, C (O) NR aR b, NR aR b or S (O) (NR c) R h1, wherein R a and R b are each independently hydrogen, R h1, C (O) H, C (O) R h1, C (O) OR h1, CONH 2, C (O) NHR h1, or C (O) NR h1R h1, or a nitrogen protecting group; or R a and R b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;R c is hydrogen or C 1-4 alkyl; andwherein R h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- The compound of claim 15 or 20, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected fromeach of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h2 or OR h2,wherein R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R s2, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C 1-4 alkoxy optionally substituted with 1-3 F.
- The compound of claim 15 or 20, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected fromeach of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h3 or OR h3,wherein R h3 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, and C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein X is O.
- The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein X is NH.
- The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Y is O.
- The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein Y is NH, a bond or CH 2.
- The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R 2 is a C 1-6 alkyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, oxo (as valency permits) , C 1-4 heteroalkyl optionally substituted with 1-3 F, C 3-6 cycloalkyl, or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, wherein the C 3-6 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with halogen (e.g., F or Cl) , OH, CN, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 heteroalkyl optionally substituted with 1-3 F.
- The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 3-6 cycloalkyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 heteroalkyl optionally substituted with 1-3 F.
- The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , R s3, OR s3, or C (O) R s3, wherein R s3 at each occurrence is independently C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4, C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4, or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted with one or more (e.g., 1, 2, or 3) R s4, wherein R s4 at each occurrence is independently F, OH, CN, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 heteroalkyl optionally substituted with 1-3 F.
- A compound of Formula II, or a pharmaceutically acceptable salt thereof:wherein:A is an optionally substituted 6-membered heteroaryl, optionally substituted 8-10 membered bicyclic heteroaryl, or optionally substituted 5-membered heteroaryl, L 2 is a bond, O, optionally substituted C 1-4 alkylene, optionally substituted C 1-4 heteroalkylene, NH,R 3 is L 3- (phenyl) , L 3- (5-10 membered heterocyclyl) or L 3- (5-10 membered heteroaryl) , wherein the phenyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl (e.g., 5-or 6-membered heteroaryl, or 8-10 membered bicyclic heteroaryl) is optionally substituted, and L 3 is a bond, an optionally substituted C 1-4 alkylene, or optionally substituted C 1-4 heteroalkylene;X is NR 10 or O;Y is a bond, O, NR 10, optionally substituted C 1-4 alkylene, or optionally substituted C 1-4 heteroalkylene;R 2 is hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or NR 11R 12;wherein:R 10 at each occurrence is independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, or optionally substituted 4-10 membered heterocyclyl;each of R 11 and R 12 is independently hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl; or a nitrogen protecting group; or R 11 and R 12, together with the nitrogen atom they are attached, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl.
- The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein A is imidazole ring.
- The compound of claim 35 or 36, or a pharmaceutically acceptable salt thereof, wherein L 2 is NH.
- The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R 3 is an optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.
- The compound of any one of claims 35-38, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h1, OR h1, C (O) R h1, C (O) H, C (O) OR h1, COOH, S (O) R h1, S (O) 2R h1, S (O) 2NR aR b, C (O) NR aR b, NR aR b or S (O) (NR c) R h1, wherein R a and R b are each independently hydrogen, R h1, C (O) H, C (O) R h1, C (O) OR h1, CONH 2, C (O) NHR h1, or C (O) NR h1R h1, or a nitrogen protecting group; or R a and R b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;R c is hydrogen or C 1-4 alkyl; andR h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h2 or OR h2,wherein R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R s2, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C 1-4 alkoxy optionally substituted with 1-3 F.
- The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:wherein the pyridyl, pyridazinyl, or pyrazinyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h3 or OR h3,wherein R h3 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5, 6-bicyclic or 6, 6-bicyclic heteroaryl having 1-4 ring heteroatoms independently selected from N, O, and S,wherein the 5, 6-bicyclic or 6, 6-bicyclic heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h1, OR h1, C (O) R h1, C (O) H, C (O) OR h1, COOH, S (O) R h1, S (O) 2R h1, S (O) 2NR aR b, C (O) NR aR b, NR aR b or S (O) (NR c) R h1, wherein R a and R b are each independently hydrogen, R h1, C (O) H, C (O) R h1, C (O) OR h1, CONH 2, C (O) NHR h1, or C (O) NR h1R h1, or a nitrogen protecting group; or R a and R b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;R c is hydrogen or C 1-4 alkyl; andR h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- The compound of claim 37 or 42, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected fromeach of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h2 or OR h2,wherein R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently halogen (e.g., F or Cl) , CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, 4-7 membered heterocyclyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, phenyl optionally substituted with one or more (e.g., 1, 2, or 3) R s2, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S optionally substituted with one or more (e.g., 1, 2, or 3) R s2, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl, and R s2 at each occurrence is independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, cyclopropyl, cyclobutyl, or C 1-4 alkoxy optionally substituted with 1-3 F.
- The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected fromeach of the foregoing bicyclic heteroaryls is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h3 or OR h3,wherein R h3 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, and C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein R 3 is CH 2-R 30 or R 30, wherein R 30 is an optionally substituted phenyl or optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.
- The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h1, OR h1, C (O) R h1, C (O) H, C (O) OR h1, COOH, S (O) R h1, S (O) 2R h1, S (O) 2NR aR b, C (O) NR aR b, NR aR b or S (O) (NR c) R h1, wherein R a and R b are each independently hydrogen, R h1, C (O) H, C (O) R h1, C (O) OR h1, CONH 2, C (O) NHR h1, or C (O) NR h1R h1, or a nitrogen protecting group; or R a and R b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;R c is hydrogen or C 1-4 alkyl; andR h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein R 30 is selected from:each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h2, S (O) 2R h2 or OR h2,wherein R h2 at each occurrence is independently a C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, or 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S,wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently F, Cl, CN, OH, oxo (as valency permits) , C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s1, wherein R s1 at each occurrence is independently F, OH, oxo (as valency permits) , methoxy, or methyl.
- The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 6-membered heteroaryl having 1-3 ring nitrogen atoms.
- The compound of claim 51 or 52, wherein L 2 is NH.
- The compound of any one of claims 51-53, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h1, OR h1, C (O) R h1, C (O) H, C (O) OR h1, COOH, S (O) R h1, S (O) 2R h1, S (O) 2NR aR b, C (O) NR aR b, NR aR b or S (O) (NR c) R h1, provided that at least one of the substituents is S (O) (NR c) R h1, S (O) 2R h1, S (O) 2NR aR b or C (O) NR aR b, wherein R a and R b are each independently hydrogen, R h1, C (O) H, C (O) R h1, C (O) OR h1, CONH 2, C (O) NHR h1, or C (O) NR h1R h1, or a nitrogen protecting group; or R a and R b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;R c is hydrogen or C 1-4 alkyl; andR h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- The compound of any one of claims 51-53, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:whereinR j is OH, halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl, andR h2 is C 1-4 alkyl or C 3-6 cycloalkyl,wherein each of the C 1-4 alkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl is optionally substituted with 1-3 F.
- The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein the NR aR b is NH 2.
- The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 5, 6-bicyclic heteroaryl having 1-4 ring nitrogen atoms.
- The compound of claim 58 or 59, wherein L 2 is NH.
- The compound of any one of claims 58-60, or a pharmaceutically acceptable salt thereof, wherein R 3 is C (R 40) (R 41) -R 42, wherein:R 40 and R 41 are independently hydrogen, deuterium, or methyl, or R 40 and R 41, together with the carbon they are both attached to, form an optionally substituted C 3-6 cycloalkyl or optionally substituted 4-8 membered heterocyclyl, andR 42 is an optionally substituted phenyl or optionally substituted 5-or 6-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S.
- The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R 40 and R 41 are the same, and both are hydrogen, deuterium, or methyl.
- The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R 40 is hydrogen, and R 41 is deuterium or methyl.
- The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R 40 and R 41, together with the carbon they are both attached to, form a cyclopropyl.
- The compound of any one of claims 61-64, or a pharmaceutically acceptable salt thereof, wherein R 42 is selected from:each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, R h1, OR h1, C (O) R h1, C (O) H, C (O) OR h1, COOH, S (O) R h1, S (O) 2R h1, S (O) 2NR aR b, C (O) NR aR b, NR aR b or S (O) (NR c) R h1, wherein R a and R b are each independently hydrogen, R h1, C (O) H, C (O) R h1, C (O) OR h1, CONH 2, C (O) NHR h1, or C (O) NR h1R h1, or a nitrogen protecting group; or R a and R b, together with the nitrogen atom they are attached to, form an optionally substituted 4-10 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl;R c is hydrogen or C 1-4 alkyl; andR h1 at each occurrence is independently an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
- The compound of claim 65, or a pharmaceutically acceptable salt thereof, wherein R 42 is selected from:each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents each independently OH, halogen, CN, C 1-4 alkyl, or C 1-4 alkoxy, wherein the C 1-4 alkyl or C 1-4 alkoxy is optionally substituted with 1-3 F.
- The compound of any one of claims 34-67, or a pharmaceutically acceptable salt thereof, wherein X is O.
- The compound of any one of claims 34-67, or a pharmaceutically acceptable salt thereof, wherein X is NH.
- The compound of any one of claims 34-69, or a pharmaceutically acceptable salt thereof, wherein Y is O.
- The compound of any one of claims 34-69, or a pharmaceutically acceptable salt thereof, wherein Y is NH, a bond or CH 2.
- The compound of any one of claims 34-73, or a pharmaceutically acceptable salt thereof, wherein R 2 is a C 1-6 alkyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, oxo (as valency permits) , C 1-4 heteroalkyl optionally substituted with 1-3 F, C 3-6 cycloalkyl, or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, wherein the C 3-6 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted with halogen (e.g., F or Cl) , OH, CN, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 heteroalkyl optionally substituted with 1-3 F.
- The compound of any one of claims 34-73, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 3-6 cycloalkyl, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 heteroalkyl optionally substituted with 1-3 F.
- The compound of any one of claims 34-73, or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted one or more (e.g., 1, 2, or 3) substituents each independently F, OH, CN, oxo (as valency permits) , R s3, OR s3, or C (O) R s3, wherein R s3 at each occurrence is independently C 1-4 alkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4, C 1-4 heteroalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4, C 3-6 cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) R s4, or 4-8 membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, optionally substituted with one or more (e.g., 1, 2, or 3) R s4, wherein R s4 at each occurrence is independently F, OH, CN, oxo (as valency permits) , C 1-4 alkyl optionally substituted with 1-3 F, or C 1-4 heteroalkyl optionally substituted with 1-3 F.
- A compound selected from those shown in Table 1A or 1B herein, or any of the compounds according to Compound Nos. I-IX herein, or a pharmaceutically acceptable salt thereof.
- A pharmaceutical composition comprising the compound of any one of claims 1-79, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-79, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 80.
- The method of claim 81, wherein the cancer is 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 (i.e., gastric) cancer and/or thyroid cancer.
- The method of claim 81, wherein the cancer is breast cancer selected from ER-positive/HR-positive, HER2-negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC) ; and inflammatory breast cancer.
- The method of claim 81, wherein the cancer is breast cancer selected from endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
- The method of claim 81, wherein the cancer is advanced or metastatic breast cancer.
- The method of claim 81, wherein the cancer is ovarian cancer.
- The method of any one of claims 81-86, wherein the cancer is characterized by an amplification or overexpression of cyclin E1 and/or cyclin E2.
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WO2023274397A1 (en) * | 2021-07-01 | 2023-01-05 | 上海拓界生物医药科技有限公司 | Cdk2 inhibitor, preparation method therefor and use thereof |
WO2023083201A1 (en) * | 2021-11-09 | 2023-05-19 | 上海拓界生物医药科技有限公司 | Aminopyrazole derivative, and preparation method therefor and use thereof |
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WO2023208143A1 (en) * | 2022-04-28 | 2023-11-02 | 正大天晴药业集团股份有限公司 | Pyrazole-substituted cyclopentanol ester derivative and use thereof |
WO2024051727A1 (en) * | 2022-09-09 | 2024-03-14 | 楚浦创制(武汉)医药科技有限公司 | Pyrazole derivative, pharmaceutical composition, and use |
WO2024059010A1 (en) * | 2022-09-13 | 2024-03-21 | Genesis Therapeutics, Inc. | Compounds for treating cancer |
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