WO2023154426A1 - Cdk inhibitors and methods of use thereof - Google Patents

Cdk inhibitors and methods of use thereof Download PDF

Info

Publication number
WO2023154426A1
WO2023154426A1 PCT/US2023/012759 US2023012759W WO2023154426A1 WO 2023154426 A1 WO2023154426 A1 WO 2023154426A1 US 2023012759 W US2023012759 W US 2023012759W WO 2023154426 A1 WO2023154426 A1 WO 2023154426A1
Authority
WO
WIPO (PCT)
Prior art keywords
nitrogen
membered
sulfur
oxygen
independently selected
Prior art date
Application number
PCT/US2023/012759
Other languages
French (fr)
Inventor
Jing He
Alexander M. Taylor
Nicolas A. PABON
Kevin David RAYNOR
Jay F. Larrow
Charles R. Heap
Original Assignee
Relay Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Relay Therapeutics, Inc. filed Critical Relay Therapeutics, Inc.
Publication of WO2023154426A1 publication Critical patent/WO2023154426A1/en

Links

Classifications

    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for inhibiting the activity of CDK enzymes with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with CDK signaling with the compounds and compositions of the disclosure.

Description

CDK INHIBITORS AND METHODS OF USE THEREOF CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 63/309,213, filed February 11, 2022, U.S. Provisional Application No. 63/325,284, filed March 30, 2022, U.S. Provisional Application No.63/348,599, filed June 3, 2022, and U.S. Provisional Application No. 63/397,136, filed August 11, 2022, each of which is herein incorporated by reference in its entirety. BACKGROUND [0002] Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases that are regulated by direct binding to cyclins. The initially-discovered CDKs (CDK1, CDK2, CDK4, CDK6) bind to cognate cyclins during specific cell cycle phases, activating their kinase activity and promoting cell cycle progression (Malumbres M. Genome Biology 2014). Related CDK family members (CDK7, CDK8, CDK9, CDK12, CDK13) are involved in other biological functions such as transcriptional control (Chou J., et al. Cancer Discovery 2020). [0003] The cell cycle is initiated following mitogenic stimuli that signal for cyclin D expression, binding to CDK4/6, and kinase activation. The active CDK4/6-cyclin D complex mono- phosphorylates the retinoblastoma protein (RB), a tumor suppressor, to initiate cyclin E expression and formation of an active CDK2-cyclin E complex. Activated CDK2-cyclin E hyper- phosphorylates RB, triggering DNA replication, which is further promoted by CDK2-cyclin A. Finally, CDK1-cyclin B and CDK1-cyclin A coordinate segregation of duplicated DNA within the mother cell to complete cell division, and form two new daughter cells (Otto, T., and Sicinski, P. Nat Rev Cancer 2017) [0004] As sustained cellular proliferation is one hallmark of cancer, alterations in pathways controlling cell cycle progression are frequently associated with cancer. Indeed, CCNE1 (gene encoding cyclin E1 protein) is among the most frequently amplified genes in variety of cancers including ovarian, endometrial, gastric, cervical, bladder, esophageal, lung, and breast cancers (Sanchez-Vega F., et al. Cell 2018; Cerami E., et al. Cancer Discovery 2012). The amplified CCNE1 gene, which leads to overexpression of cyclin E1 protein, is believed to be the oncogenic driver in those tumors due to increased CDK2-cyclin E activity. Notably, CCNE1 amplified or overexpressed tumor cells are dependent on CDK2 activity and thus provide the rationale for targeting CDK2 in this genetically defined patient population (McDonald E.R., et al Cell 2017; Au-Yeung G., et al. Clin Cancer Research 2016). Furthermore, CDK2 activation via Cyclin E1 amplification and overexpression is a common mechanism of resistance to several approved targeted therapies (such as CDK4/6 and HER2 modulators), and therefore supports combined targeting of CDK2 with other validated drivers in cancer (Turner N.C., et al. J Clin Oncology 2019; Herrera-Abreu M.T., et al. Cancer Research 2016; Scaltriti M., et al. PNAS 2011). [0005] Multiple pan-CDK inhibitors with activity against CDK2 and other CDKs have shown evidence of clinical activity, however they have also shown significant hematopoietic and gastrointestinal toxicities likely due to their inhibition of CDK1 (Otto, T., and Sicinski, P., Nat. Review Cancer 2017; Kumar, K.S., et al. Blood 2015; Shapiro G.I., et al. Clin Cancer Research 2001). Whereas CDK2 activity may be dispensable for normal cell function, CDK1 activity is essential in all cells, especially in the highly proliferating cells of the gut and the hematopoietic system (Berthet C., et al. Current Biology 2003; Jayapal S.R., et al. Haematologica 2015; Santamaria D., et al. Nature 2007; Lu S., et al. Tox Sciences 2020). SUMMARY [0006] In some embodiments, the present disclosure encompasses the recognition that there is a need for CDK-selective inhibitor compounds, e.g., CDK2-selective inhibitor compounds, and methods for treating cancers and other disorders with these compounds. [0007] In some embodiments, the present disclosure provides a compound of formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyA, CyB, CyC, Q, and P is as defined in embodiments and classes and subclasses herein. [0008] In some embodiments, the present disclosure provides a compound of formula I-A:
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyB, CyC, Q, and P is as defined in embodiments and classes and subclasses herein. [0009] In some embodiments, the present disclosure provides a compound of formula II or III:
Figure imgf000004_0002
or a pharmaceutically acceptable salt thereof, wherein each of CyB, CyC, RP, Q, X, and Y is as defined in embodiments and classes and subclasses herein. [0010] In some embodiments, the present disclosure provides a compound of formula IV-a, IV-b, IV-c, V-a, V-b, or V-c:
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyC, RP, and Q is as defined in embodiments and classes and subclasses herein. [0011] In some embodiments, the present disclosure provides a compound of formula VI, VII, VIII, IX, X, XI, XII, or XIII:
Figure imgf000005_0002
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyC and RP is as defined in embodiments and classes and subclasses herein. [0012] In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, or XIX:
Figure imgf000006_0002
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyC, RP1, and Q is as defined in embodiments and classes and subclasses herein. [0013] In some embodiments, the present disclosure provides a compound of formula XX, XXI, XXII:
Figure imgf000007_0002
or a pharmaceutically acceptable salt thereof, wherein each of CyC, RC1, RP, and Q is as defined in embodiments and classes and subclasses herein. [0014] In some embodiments, the present disclosure provides a compound of formula XXIII, XXIV, or XXV:
Figure imgf000007_0003
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, wherein each of RC1, RP, and Q is as defined in embodiments and classes and subclasses herein. [0015] In some embodiments, the present disclosure provides a compound of formula XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, or XXVII-c:
Figure imgf000008_0002
or a pharmaceutically acceptable salt thereof, wherein each of CyC, RP, and Q is as defined in embodiments and classes and subclasses herein. [0016] In some embodiments, the present disclosure provides a compound of formula XXVIII:
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyA, CyB, CyC, Q, P, and RD is as defined in embodiments and classes and subclasses herein. [0017] As described generally above, in some embodiments, the present disclosure provides a compound of formula XXIX or XXX:
Figure imgf000009_0002
or a pharmaceutically acceptable salt thereof, wherein each of CyB, CyC, RD, Q, X, Y, and RP is as defined in embodiments and classes and subclasses herein. [0018] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the disclosure, for example, a compound of formula I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII, XXIX, or XXX, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the disclosure, for example, a compound of formula I-A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent. [0019] In some embodiments, the present disclosure provides a method of treating a CDK2- mediated disorder comprising administering to a patient in need thereof a compound of formula I, or composition comprising said compound. In some embodiments, the present disclosure provides a method of treating a CDK2-mediated disorder comprising administering to a patient in need thereof a compound of the disclosure, for example, a compound of formula I-A, II, III, IV-a, IV- b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII, XXIX, or XXX, or composition comprising said compound. In some embodiments, the present disclosure provides a method of treating a CDK2-mediated disorder comprising administering to a patient in need thereof a compound of the disclosure, for example, a compound of formula I-A II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII, XXIX, or XXX,, or composition comprising said compound. [0020] In some embodiments, the present disclosure provides a process for providing a compound of formula I, or synthetic intermediates thereof. In some embodiments, the present disclosure provides a process for providing a compound of the disclosure, for example, a compound of formula I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII, XXIX, or XXX, or synthetic intermediates thereof. In some embodiments, the present disclosure provides a process for providing a compound of the disclosure, for example, a compound of formula I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII, XXIX, or XXX, or synthetic intermediates thereof. [0021] In some embodiments, the present disclosure provides a process for providing pharmaceutical compositions comprising compounds of formula I. In some embodiments, the present disclosure provides a process for providing pharmaceutical compositions comprising compounds of the disclosure, for example, a compound of formula I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII, XXIX, or XXX,. In some embodiments, the present disclosure provides a process for providing pharmaceutical compositions comprising compounds of the disclosure, for example, a compound of formula I, I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII, XXIX, or XXX. DETAILED DESCRIPTION 1. General Description of Certain Embodiments [0022] Compounds provided herein, and pharmaceutical compositions thereof, are useful as inhibitors of CDK2. In some embodiments, the present disclosure provides a compound of formula I:
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein: Q is L1; CyA is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyA is substituted with m instances of RA in addition to Q and CyB; CyB is
Figure imgf000011_0002
represents a covalent bond to CyA and
Figure imgf000011_0003
represents a covalent bond to P; P is L2-RP; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to L2; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q; RC is L3-RC1 or L3-H; RC1 is C1-4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1–4 haloalkyl, C1–4 alkoxy, and C1–4 haloalkoxy; each instance of RA or RB is independently R1 or R2, wherein RA is substituted by qA instances of R3, RB is substituted by qB instances of R3, or two instances of RA, two instances of RB, two instances of RC, an instance of RA and an instance of RL, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each of L1, L2, and L3 is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1–6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1–6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of m, n, p, qA, qB, qP, r, and t is independently 0, 1, 2, 3, or 4. [0023] In some embodiments, the present disclosure provides a compound of formula I-A:
Figure imgf000014_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyB, CyC, Q, and P is as defined in embodiments and classes and subclasses herein. [0024] In some embodiments, the present disclosure provides a compound of formula II or III:
Figure imgf000014_0002
or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, NRX, and S; Y is selected from O, NRY, and S; each instance of RX and RY is independently R; Q is L1; CyB is
Figure imgf000015_0001
, , , represents a covalent bond to X; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to X or Y; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q; RC is L3-RC1 or L3-H; RC1 is C1-4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1–4 haloalkyl, C1–4 alkoxy, and C1–4 haloalkoxy; each instance of RB is independently R1 or R2, wherein RB is substituted by qB instances of R3, or two instances of RB, two instances of RC, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each of L1 and L3 is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1-6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1–6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, qB, qP, r, and t is independently 0, 1, 2, 3, or 4. [0025] In some embodiments, the present disclosure provides a compound of formula IV-a, IV-b, IV-c, V-a, V-b, or V-c:
Figure imgf000017_0001
Figure imgf000018_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyC, RP, and Q is as defined in embodiments and classes and subclasses herein. [0026] In some embodiments, the present disclosure provides a compound of formula VI, VII, VIII, IX, X, XI, XII, or XIII:
Figure imgf000018_0002
Figure imgf000019_0002
or a pharmaceutically acceptable salt thereof, wherein each of CyC and RP is as defined in embodiments and classes and subclasses herein. [0027] In some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, or XIX: ,
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyC, RP1, and Q is as defined in embodiments and classes and subclasses herein. [0028] In some embodiments, the present disclosure provides a compound of formula XX, XXI, XXII:
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyC, RC1, RP, and Q is as defined in embodiments and classes and subclasses herein. [0029] In some embodiments, the present disclosure provides a compound of formula XXIII, XXIV, or XXV:
Figure imgf000020_0002
or a pharmaceutically acceptable salt thereof, wherein each of RC1, RP, and Q is as defined in embodiments and classes and subclasses herein. [0030] In some embodiments, the present disclosure provides a compound of formula XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, or XXVII-c:
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyC, RP, and Q is as defined in embodiments and classes and subclasses herein. [0031] In some embodiments, the present disclosure provides a compound of formula XXVIII:
Figure imgf000021_0002
or a pharmaceutically acceptable salt thereof, wherein each of CyA, CyB, CyC, Q, P, and RD is as defined in embodiments and classes and subclasses herein. [0032] As described generally above, in some embodiments, the present disclosure provides a compound of formula XXIX or XXX:
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof, wherein each of CyB, CyC, RD, Q, X, Y, and RP is as defined in embodiments and classes and subclasses herein. 2. Compounds and Definitions [0033] Compounds described herein include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. [0034] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. A carbocycle can be, under certain circumstances, a bridged bicyclic or a fused ring such as, e.g., an ortho-fused carbocycle, a spirofused carbocycle, etc. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0035] The term “alkyl”, unless otherwise indicated, as used herein, refers to a monovalent aliphatic hydrocarbon radical having a straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof, wherein the radical is optionally substituted at one or more carbons of the straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof with one or more substituents at each carbon, wherein the one or more substituents are independently C1-C10 alkyl. Examples of “alkyl” groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. [0036] The term “lower alkyl” refers to a C1–4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0037] The term “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms. Exemplary haloalkyl groups are -CF3, -CHF2, -CH2F, and the like. [0038] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0039] The term “alkoxy” refers to an alkyl group covalently attached to an oxygen atom, wherein the oxygen atom is the intervening atom between the alkyl group and another point of attachment. Exemplary alkoxy groups are -OMe (i.e., “methoxy”), -OEt (i.e., “ethoxy”), and the like. [0040] The term “haloalkoxy” refers to an alkyl group substituted with one or more halogen atoms, wherein the alkyl group is covalently attached to an oxygen atom, and wherein the oxygen atom is the intervening atom between the alkyl group and another point of attachment. Exemplary haloalkoxy groups are -OCF3, -OCHF2, -OCH2CH2F, -OCH(F)CH3, and the like. [0041] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)). [0042] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0043] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0044] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0045] The term “halogen” means F, Cl, Br, or I. [0046] The term “aryl,” used alone or as part of a larger moiety, refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of compounds described herein, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. It will be appreciated that an “aryl” group can comprise carbon and heteroatom ring members. [0047] The terms “heteroaryl” or “heteroaromatic”, unless otherwise defined, as used herein refers to a monocyclic aromatic 5-6 membered ring containing one or more heteroatoms, for example one to four heteroatoms, such as nitrogen, oxygen, and sulfur, or an 8-10 membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring in the polycyclic ring system is aromatic, and the point of attachment of the polycyclic ring system is through a ring atom on an aromatic ring. A heteroaryl ring may be linked to adjacent radicals though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, etc. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a heteroaryl ring if its point of attachment is through the benzo ring, e.g.:
Figure imgf000025_0001
. [0048] The terms “heterocyclyl” or “heterocyclic group”, unless otherwise defined, refer to a saturated or partially unsaturated 3-10 membered monocyclic or 7-14 membered polycyclic ring system, including bridged or fused rings (e.g., an ortho-fused bicyclic or a spirofused bicyclic ring), and whose ring system includes one to four heteroatoms, such as nitrogen, oxygen, and sulfur. A heterocyclyl ring may be linked to adjacent radicals through carbon or nitrogen. [0049] The term “partially unsaturated” in the context of rings, unless otherwise defined, refers to a monocyclic ring, or a component ring within a polycyclic (e.g. bicyclic, tricyclic, etc.) ring system, wherein the component ring contains at least one degree of unsaturation in addition to those provided by the ring itself, but is not aromatic. Examples of partially unsaturated rings include, but are not limited to, 3,4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, etc. Where a partially unsaturated ring is part of a polycyclic ring system, the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a partially unsaturated component ring. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring if its point of attachment is through the piperidino ring, e.g.:
Figure imgf000025_0002
. [0050] The term “saturated” in the context of rings, unless otherwise defined, refers to a 3-10 membered monocyclic ring, or a 7-14 membered polycyclic (e.g. bicyclic, tricyclic, etc.) ring system, wherein the monocyclic ring or the component ring that is the point of attachment for the polycyclic ring system contains no additional degrees of unsaturation in addition to that provided by the ring itself. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, etc. Where a saturated ring is part of a polycyclic ring system, the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a saturated component ring. For example, unless otherwise defined, 2-azaspiro[3.4]oct-6-ene is a saturated ring if its point of attachment is through the azetidino ring, e.g.:
Figure imgf000026_0001
. [0051] The terms “alkylene”, “arylene”, “cycloalkylene”, “heteroarylene”, “heterocycloalkylene”, and the other similar terms with the suffix “-ylene” as used herein refers to a divalently bonded version of the group that the suffix modifies. For example, “alkylene” is a divalent alkyl group connecting the groups to which it is attached. [0052] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:
Figure imgf000027_0001
[0053] As described herein, compounds described herein may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0054] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4Rº; –(CH2)0–4ORº; -O(CH2)0-4Rº, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(ORº)2; –(CH2)0–4SRº; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(Rº)2; –(CH2)0–4N(Rº)C(O)Rº; –N(Rº)C(S)Rº; –(CH2)0–4N(Rº)C(O)NRº2; -N(Rº)C(S)NRº2; –(CH2)0–4N(Rº)C(O)ORº; –N(Rº)N(Rº)C(O)Rº; -N(Rº)N(Rº)C(O)NRº2; -N(Rº)N(Rº)C(O)ORº; –(CH2)0–4C(O)Rº; –C(S)Rº; –(CH2)0–4C(O)ORº; –(CH2)0–4C(O)SRº; -(CH2)0–4C(O)OSiRº3; –(CH2)0–4OC(O)Rº; –OC(O)(CH2)0–4SR°; –SC(S)SR°; –(CH2)0–4SC(O)Rº; –(CH2)0–4C(O)NRº2; –C(S)NRº2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NRº2; -C(O)N(ORº)Rº; –C(O)C(O)Rº; –C(O)CH2C(O)Rº; –C(NORº)Rº; -(CH2)0–4SSRº; –(CH2)0–4S(O)2Rº; –(CH2)0–4S(O)2ORº; –(CH2)0–4OS(O)2Rº; –S(O)2NRº2; -(CH2)0–4S(O)Rº; -N(Rº)S(O)2NRº2; –N(Rº)S(O)2Rº; –N(ORº)Rº; –C(NH)NRº2; –P(O)(ORº)Rº; -P(O)Rº2; -OP(O)Rº2; –OP(O)(ORº)2; –SiRº3; –(C1–4 straight or branched alkylene)O–N(Rº)2; or –(C1–4 straight or branched alkylene)C(O)O– N(Rº)2, wherein each Rº may be substituted as defined below and is independently hydrogen, C1– 6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 3–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rº, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [0055] Suitable monovalent substituents on Rº (or the ring formed by taking two independent occurrences of Rº together with their intervening atoms), are independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2; -O(haloR●), –CN, –N3, –(CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR●, –(CH2)0–2NR●2, –NO2, –SiR● 3, –OSiR● 3, -C(O)SR●, –(C1–4 straight or branched alkylene)C(O)OR●, or –SSR● wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of Rº include =O and =S. [0056] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR* 2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R* 2))2–3O–, or –S(C(R* 2))2–3S–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR* 2)2– 3O–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0057] Suitable substituents on the aliphatic group of R* include halogen, –R ●, -(haloR ●), -OH, –OR ●, –O(haloR ●), –CN, –C(O)OH, –C(O)OR ●, –NH2, –NHR ●, –NR ●2, or –NO2, wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0058] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR† 2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR† 2, –C(S)NR† 2, –C(NH)NR† 2, or –N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0059] Suitable substituents on the aliphatic group of R† are independently halogen, –R ●, -(haloR ●), –OH, –OR ●, –O(haloR ●), –CN, –C(O)OH, –C(O)OR ●, –NH2, –NHR ●, –NR ● 2, or -NO2, wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0060] The term “isomer” as used herein refers to a compound having the identical chemical formula but different structural or optical configurations. The term “stereoisomer” as used herein refers to and includes isomeric molecules that have the same molecular formula but differ in positioning of atoms and/or functional groups in the space. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this disclosure. Therefore, unless otherwise stated, single stereochemical isomers as well as mixtures of enantiomeric, diastereomeric, and geometric (or conformational) isomers of the present compounds are within the scope of the disclosure. [0061] The term “tautomer” as used herein refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as prototropic tautomers). Valence tautomers include interconversions by reorganization of some of the bonding electrons. Proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Unless otherwise stated, all tautomers of the compounds described herein are within the scope of the disclosure. [0062] The term “isotopic substitution” as used herein refers to the substitution of an atom with its isotope. The term “isotope” as used herein refers to an atom having the same atomic number as that of atoms dominant in nature but having a mass number (neutron number) different from the mass number of the atoms dominant in nature. It is understood that a compound with an isotopic substitution refers to a compound in which at least one atom contained therein is substituted with its isotope. Atoms that can be substituted with its isotope include, but are not limited to, hydrogen, carbon, and oxygen. Examples of the isotope of a hydrogen atom include 2H (also represented as D) and 3H. Examples of the isotope of a carbon atom include 13C and 14C. Examples of the isotope of an oxygen atom include 18O. Unless otherwise stated, all isotopic substitution of the compounds described herein are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. [0063] As used herein, 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. Exemplary pharmaceutically acceptable salts are found, e.g., in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1; and Gould, P.L., Int. J. Pharmaceutics 1986, 33, 201-217; (each hereby incorporated by reference in its entirety). [0064] Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [0065] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [0066] Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is respectively 2:1. Exemplary hemi-salts are those salts derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary hemi-salts are those salts derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate. [0067] As used herein the term “about” is used herein to mean approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower). [0068] An “effective amount”, “sufficient amount” or “therapeutically effective amount” as used herein is an amount of a compound that is sufficient, when administered to a subject or population suffering from or susceptible to a disease, disorder, and/or condition in accordance with a therapeutic dosing regimen, to treat (e.g., effect beneficial or desired results, including clinical results) the disease, disorder, and/or condition. As such, the effective amount may be sufficient, e.g., to reduce or ameliorate the severity and/or duration of afflictions related to CDK2 signaling, or one or more symptoms thereof, prevent the advancement of conditions or symptoms related to afflictions related to CDK2 signaling, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects. [0069] As used herein and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminution of extent of disease or affliction, a stabilized (i.e., not worsening) state of disease or affliction, preventing spread of disease or affliction, delay or slowing of disease or affliction progression, amelioration or palliation of the disease or affliction state and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. [0070] The phrase “in need thereof” refers to the need for symptomatic or asymptomatic relief from conditions related to CDK2 signaling activity or that may otherwise be relieved by the compounds and/or compositions of the disclosure. 3. Description of Exemplary Embodiments [0071] As described generally above, in some embodiments, the present disclosure provides a compound of formula I:
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein: Q is L1; CyA is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyA is substituted with m instances of RA in addition to Q and CyB; CyB is
Figure imgf000033_0002
represents a covalent bond to CyA and
Figure imgf000033_0003
represents a covalent bond to P; P is L2-RP; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to L2; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q; RC is L3-RC1 or L3-H; RC1 is C1-4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1–4 haloalkyl, C1–4 alkoxy, and C1–4 haloalkoxy; each instance of RA or RB is independently R1 or R2, wherein RA is substituted by qA instances of R3, and RB is substituted by qB instances of R3, or two instances of RA, two instances of RB, two instances of RC, an instance of RA and an instance of RL, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each of L1, L2, and L3 is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1–6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1–6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of m, n, p, qA, qB, qP, r, and t is independently 0, 1, 2, 3, or 4. [0072] As described generally above, in some embodiments, the present disclosure provides a compound of formula II or III:
Figure imgf000036_0001
or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, NRX, and S; Y is selected from O, NRY, and S; each instance of RX and RY is independently R; Q is L1; CyB is
Figure imgf000036_0002
represents a covalent bond to X; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to X or Y; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q; RC is L3-RC1 or L3-H; RC1 is C1-4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1–4 haloalkyl, C1–4 alkoxy, and C1–4 haloalkoxy; each instance of RB is independently R1 or R2, wherein RB is substituted by qB instances of R3, or two instances of RB, two instances of RC, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each of L1 and L3 is independently is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1-6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1–6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, qB, qP, r, and t is independently 0, 1, 2, 3, or 4. [0073] As described generally above, in some embodiments, the present disclosure provides a compound of formula IV-a, IV-b, IV-c, V-a, V-b, or V-c:
Figure imgf000039_0001
or a pharmaceutically acceptable salt thereof, wherein: Q is L1; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q; RC is L3-RC1 or L3-H; RC1 is C1-4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1–4 haloalkyl, C1–4 alkoxy, and C1–4 haloalkoxy; or two instances of RC, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each of L1, L2 , and L3 is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1–6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of p, qP, r, and t is independently 0, 1, 2, 3, or 4. [0074] As described generally above, in some embodiments, the present disclosure provides a compound of formula VI, VII, VIII, IX, X, XI, XII, or XIII:
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof, wherein: RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC; RC is L3-RC1 or L3-H; RC1 is C1-4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1–4 haloalkyl, C1–4 alkoxy, and C1–4 haloalkoxy; two instances of RC, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each L3 is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1–6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of p, qP, r, and t is independently 0, 1, 2, 3, or 4. [0075] As described generally above, in some embodiments, the present disclosure provides a compound of formula XIV, XV, XVI, XVII, XVIII, or XIX: ,
Figure imgf000045_0001
or a pharmaceutically acceptable salt thereof, wherein: Q is L1; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q; RC is L3-RC1 or L3-H; RC1 is C1–4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; two instances of RC, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each of L1, and L3 is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1-6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of p, r, and t is independently 0, 1, 2, 3, or 4. [0076] As described generally above, in some embodiments, the present disclosure provides a compound of formula XX, XXI, XXII:
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof, wherein: Q is L1; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RC1 is C1-4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; L1, is a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1-6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of qP, r, and t is independently 0, 1, 2, 3, or 4.. [0077] As described generally above, in some embodiments, the present disclosure provides a compound of formula XXIII, XXIV, or XXV:
Figure imgf000050_0001
or a pharmaceutically acceptable salt thereof, wherein: Q is L1; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1; RP1 is R3; RC1 is C1–4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; L1 is a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1–6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of qP and t is independently 0, 1, 2, 3, or 4. [0078] As described generally above, in some embodiments, the present disclosure provides a compound of formula XXVIII:
Figure imgf000052_0001
or a pharmaceutically acceptable salt thereof, wherein: RD is RD’,
Figure imgf000053_0001
RD’ is a group capable of being cleaved; each of RD1 and RD2 is independently hydrogen, R1, or R2, wherein RD1 is substituted with qD1 instances of R3, and RD2 is substituted with qD2 instances of R3; or an instance of RD1 and an instance of RD2 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with qDD instances of R3; RD3 is hydrogen, R1, or R2, wherein RD3 is substituted by qD3 instances of R3; Q is L1; CyA is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyA is substituted with m instances of RA in addition to Q and CyB; CyB is
Figure imgf000053_0002
wherein represents a covalen A
Figure imgf000053_0004
t bond to Cy and
Figure imgf000053_0003
represents a covalent bond to P; P is L2-RP; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to L2; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q; RC is L3-RC1 or L3-H; RC1 is C1–4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each instance of RA or RB is independently R1 or R2, wherein RA is substituted by qA instances of R3, and RB is substituted by qB instances of R3, or two instances of RA, two instances of RB, two instances of RC, an instance of RA and an instance of RL, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each of LD, L1, L2, and L3 is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, phenylene, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said phenylene, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is substituted with 0-3 instances of R1 or C1-6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1–6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of m, n, p, qA, qB, qD1, qD2, qD3, qDD, qP, r, and t is independently 0, 1, 2, 3, or 4. [0079] As described generally above, in some embodiments, the present disclosure provides a compound of formula XXIX or XXX:
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, NRX, and S; Y is selected from O, NRY, and S; each instance of RX and RY is independently R; RD is RD’,
Figure imgf000056_0002
RD’ is a group capable of being cleaved each of RD1 and RD2 is independently hydrogen, R1, or R2, wherein RD1 is substituted with qD1 instances of R3, and RD2 is substituted with qD2 instances of R3; or an instance of RD1 and an instance of RD2 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with qDD instances of R3; RD3 is hydrogen, R1, or R2, wherein RD3 is substituted by qD3 instances of R3; Q is L1;
Figure imgf000057_0001
wherein represents a covalent bond to CyA and
Figure imgf000057_0002
represents a covalent bond to X; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to X or Y; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q; RC is L3-RC1 or L3-H; RC1 is C1–4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each instance of RB is independently R1 or R2, wherein RB is substituted by qB instances of R3, or two instances of RB, two instances of RC, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each of LD, L1, and L3 is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, phenylene, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said phenylene, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is substituted with 0-3 instances of R1 or C1-6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, qB, qD1, qD2, qD3, qDD, qP, r, and t is independently 0, 1, 2, 3, or 4. [0080] As defined generally above, CyA is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyA is substituted with m instances of RA in addition to Q and CyB. In some embodiments, CyA is
Figure imgf000059_0001
,
Figure imgf000059_0002
, , , , , ,
Figure imgf000059_0003
represents a covalent bond to Q and
Figure imgf000059_0004
represents a covalent bond to CyB. In some embodiments, CyA is
Figure imgf000059_0005
Figure imgf000060_0005
. [0081] In some embodiments, CyA is
Figure imgf000060_0006
, wherein wherein
Figure imgf000060_0001
represents a covalent bond to Q, represents a covalent bond to CyB, and represents a c D
Figure imgf000060_0007
ovalent bond to R . [0082] In some embodiments, CyA is selected from the groups depicted in the compounds in Table 1. [0083] As generally defined above with respect to, e.g., Formulae I, I-A, and II, CyB is
Figure imgf000060_0002
represents a covalent bond to CyA and represents a covalent bond to P. As general defined above with respect to, e.g., Formulae XXVIII, XXIX, and XXX, CyB
Figure imgf000060_0003
,
Figure imgf000060_0004
represents a covalent bond to CyA and represents a covalent bond to X. [0084] In some embodiments, CyB is
Figure imgf000061_0001
. In some embodiments, CyB is
Figure imgf000061_0002
. In
Figure imgf000061_0006
[0085] In some embodiments, CyB is
Figure imgf000061_0007
, , , ,
Figure imgf000061_0008
Figure imgf000061_0009
represents a covalent bond to CyA and
Figure imgf000061_0010
represents a covalent bond to P, X, or Y. In some embodiments, CyB is
Figure imgf000061_0003
. In some embodiments, CyB is
Figure imgf000061_0004
. In some embodiments, CyB is
Figure imgf000061_0005
. In some embodiments, CyB is
Figure imgf000062_0001
Figure imgf000063_0001
[0086] In some embodiments of CyB, CyA and P or X are in a trans-relationship. In some embodiments of CyB, CyA and P or X are in a cis-relationship. See, for example, the CyB groups depicted in the compounds in Table 1. [0087] In some embodiments, CyB is selected from the groups depicted in the compounds in Table 1. [0088] As defined generally above, P is L2-RP, wherein each of L2 and RP is as defined in embodiments and classes and subclasses herein. In some embodiments, P is -L2-RP. In some embodiments, P is -ORP, -NHRP, -SRP, -NHC(O)NHRP, -OC(O)NHRP, and -NHC(O)ORP. [0089] In some embodiments, P is -XC(O)YRP, wherein each of X, Y, and RP is as defined in embodiments and classes and subclasses herein. In some embodiments, each P is selected from the groups depicted in the compounds in Table 1. [0090] As defined generally above, RP is is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to L2. [0091] In some embodiments, RP is a group selected from phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to L2. In some embodiments, RP is C1-3 aliphatic substituted with qP instances of RP1 [0092] . In some embodiments, RP is an C1-8 aliphatic substituted with qP instances of RP1. In some such embodiments, RP is C1-6 aliphatic substituted with qP instances of RP1. In some such embodiments, RP is C1-4 aliphatic substituted with qP instances of RP1 In some embodiments, RP is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -CH2CH(CH3)2, -C(CH3)3,
Figure imgf000064_0002
, , or
Figure imgf000064_0003
. some embodiments, RP is
Figure imgf000064_0004
. In some embodiments, RP is
Figure imgf000064_0005
or
Figure imgf000064_0006
[0093] In some embodiments, RP is a saturated or partially unsaturated 3-14 membered carbocyclic ring substituted with qP instances of RP1. In some embodiments, RP is a saturated or partially unsaturated 4-14 membered carbocyclic ring substituted with qP instances of RP1.In some embodiments, RP is saturated 3-membered carbocyclic ring substituted with qP instances of RP1. In some embodiments, RP is a saturated or partially unsaturated 4 membered carbocyclic ring substituted with qP instances of RP1. In some embodiments, RP is
Figure imgf000064_0001
. In some embodiments, RP is
Figure imgf000065_0001
. In some embodiments, RP is
Figure imgf000065_0002
. In some embodiments, RP is
Figure imgf000065_0003
[0094] In some embodiments, RP is a phenyl ring substituted with qP instances of RP1. In some embodiments, RP is an 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1. In some embodiments, RP is an 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1. In some such embodiments, RP is P
Figure imgf000065_0004
In some such embodiments, R is
Figure imgf000065_0006
In some such embodiments, RP is
Figure imgf000065_0005
[0095] In some embodiments, RP is an 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1. In some embodiments, RP is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1. In some such embodiments, RP is
Figure imgf000066_0002
o . In some such embodiments, RP is
Figure imgf000066_0003
. [0096] In some embodiments, RP is an 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1. In some such embodiments, RP is
Figure imgf000066_0004
[0097] In some embodiments, RP is an 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1. In some embodiments, RP is an optionally substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1. In some embodiments, RP is an 6-membered heteroaryl ring having 1-2 nitrogen atoms, substituted with qP instances of RP1. In some embodiments, RP is selected from isothiazolyl, pyridinyl, or pyridazinyl, substituted with qP instances of RP1. In some such embodiments, RP is
Figure imgf000066_0001
. [0098] In some embodiments, RP is selected from the groups depicted in the compounds in Table 1. [0099] As defined generally above, L2 is a covalent bond, or a C1-5 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1-6 aliphatic. [00100] In some embodiments, L2 is a covalent bond. In some embodiments, L2 is a C1-5 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1–6 aliphatic. In some embodiments, L2 is -CH2-. In some embodiments, L2 is -CH2O-. [00101] In some embodiments, L2 is -O-, -NH-, -S-, -NHC(O)NH-, -N(CH3)C(O)NH-*, - OC(O)NH-*, -OC(O)N(CH3)-*, -NHC(O)O-*, –CH2C(O)NH-*,–CH2OC(O)NH-*, –C(O)NH-*, and –C(O)O-*, )-, wherein “-*” represents a covalent bond to RP. In some embodiments, L2 is -O- , -NH-, -S-, -NHC(O)NH-, -N(CH3)C(O)NH-*, -OC(O)NH-*, -OC(O)N(CH3)-*, -NHC(O)O-*, – CH2C(O)NH-*, –NHC(O)CH2-*, –CH2OC(O)NH-*, –C(O)NH-*, –NHC(O)-*, –C(O)O-*, – OC(O)-*, -NHS(O)2-*, -NHS(O)2NH-*, and -OC(O)N(iPr)-*, wherein “-*” represents a covalent bond to RP. In some embodiments, L2 is -O-. In some embodiments, L2 is -NH-. In some embodiments, L2 is -S-. In some embodiments, L2 is -NHC(O)NH-. In some embodiments, L2 is - N(CH3)C(O)NH-*. In some embodiments, L2 is -OC(O)NH-*. In some embodiments, L2 is -NHC(O)O-*. In some embodiments, L2 is–CH2C(O)NH-*. In some embodiments, L2 is – CH2OC(O)NH-*. In some embodiments, L2 is –C(O)NH-*. In some embodiments, L2 is – NHC(O)-*. In some embodiments, L2 is –C(O)O-*. In some embodiments, L2 is –OC(O)-*. In some embodiments, L2 is –NHC(O)CH2-*. In some embodiments, L2 is -NHS(O)2-*. In some embodiments, L2 is -NHS(O)2NH-*. In some embodiments, L2 is -OC(O)N(iPr)-*. In some embodiments, L2 is a covalent bond, -CH2-, -NH-, -O-, -NHC(O)NH-,
Figure imgf000068_0002
, , , , ,
Figure imgf000068_0003
wherein represents a covalent bond to CyB and
Figure imgf000068_0004
represents a covalent bond to RP. In some embodiments, L2 is
Figure imgf000068_0001
, wherein
Figure imgf000068_0005
represents a covalent bond to CyB and
Figure imgf000068_0006
represents a covalent bond to RP. In some embodiments, L2 is
Figure imgf000068_0008
, wherein
Figure imgf000068_0007
represents a covalent bond to CyB and P
Figure imgf000068_0009
represents a covalent bond to R . [00102] In some embodiments, L2 is -XC(O)Y-, wherein each of X and Y is as defined in embodiments and classes and subclasses herein. In some embodiments, X is –O-. In some embodiments, X is –NRX-. In some embodiments, X is –NH-. In some embodiments, X is – N(CH3)-. In some embodiments, X is –S-. In some embodiments, Y is –O-. In some embodiments, Y is –NRY-. In some embodiments, Y is –NH-. In some embodiments, Y is – N(CH3)-. In some embodiments, Y is –S-. [00103] In some embodiments, each L2 is selected from the groups depicted in the compounds in Table 1. [00104] As defined generally above, Q is L1, wherein L1 is as defined in embodiments and classes and subclasses herein. In some embodiments, Q is a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1-6 aliphatic. In some embodiments, Q is -NH-,
Figure imgf000069_0001
or represents a covalent bond to A
Figure imgf000069_0002
Cy and
Figure imgf000069_0003
represents a covalent bond to CyC. In some embodiments, Q is -NH-. In some embodiments, Q is -O-. In some embodiments, Q is
Figure imgf000069_0004
. In some embodiments, Q is
Figure imgf000069_0005
. In some embodiments, Q is
Figure imgf000069_0006
. In some embodiments, Q is –NHC(O)NH-. In some embodiments, Q is
Figure imgf000069_0007
. In some embodiments, Q is
Figure imgf000069_0008
. [00105] In some embodiments, Q is selected from the groups depicted in the compounds in Table 1. [00106] As defined generally above, L1 is a covalent bond, or a C1-5 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1–6 aliphatic. [00107] In some embodiments, L1 is a covalent bond. In some embodiments, L1 is a C1-5 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1-6 aliphatic. [00108] In some embodiments, L1 is a -NH-,
Figure imgf000070_0001
, , ,
Figure imgf000070_0002
, , , represents a covalent bond to CyA and represents a covalent bond to CyC. In some embodiments, L1 is -NH-. In some embodiments, L1 is -O-. In some embodiments, L1 is
Figure imgf000070_0003
. In some embodiments, L1 is
Figure imgf000070_0004
. [00109] In some embodiments, L1 is selected from the groups depicted in the compounds in Table 1. [00110] As defined generally above, each instance of RL is independently R1 or R2, and is substituted by t instances of R3. In some embodiments, RL is R1. In some embodiments, RL is R2. [00111] As defined generally above, each instance of RA and RB is independently R1 or R2, wherein RA is substituted by qA instances of R3, RB is substituted by qB instances of R3. In some embodiments, RA is R1. In some embodiments, RB is R1. In some embodiments, RA is R2. In some embodiments, RB is R2. [00112] As defined generally above, RC is L3-RC1 or L3-H. In some embodiments, RC is L3-RC1. In some embodiments, RC is L3-H. [00113] In some embodiments, RC is selected from the groups depicted in the compounds in Table 1. [00114] As defined generally above, L3 is a covalent bond, or a C1-5 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1–6 aliphatic. [00115] In some embodiments, L3 is a covalent bond. In some embodiments, L3 is a C1-5 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1-6 aliphatic. [00116] In some embodiments, L3 is -OCH2-* or -CH2O-*, wherein
Figure imgf000071_0001
represents a covalent bond to RC1 or -H. In some embodiments, L3 is -OCH2-*. In some embodiments, L3 is -CH2O-*. [00117] In some embodiments, L3 is selected from the groups depicted in the compounds in Table 1. [00118] As defined generally above, LD is a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, phenylene, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said phenylene, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is substituted with 0-3 instances of R1 or C1–6 aliphatic. [00119] In some embodiments, LD is a covalent bond. In some embodiments, LD is a C1-5 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1-6 aliphatic. [00120] In some embodiments, LD is –OC1–4 alkyl-*, –OC1-3 alkyl-*, –OC2-3 alkyl-*, or –OC1-2 alkyl-*, wherein “-*” represents a covalent bond to CyA. In some embodiments, LD is –OC1-4 alkyl-*. In some embodiments, LD is –OC1-3 alkyl-*. In some embodiments, LD is –OC2-3 alkyl-*. In some embodiments, LD is –OC1-2 alkyl-*. [00121] In some embodiments, LD is -OCH2-* or -CH2O-*, wherein “-*” represents a covalent bond to CyA. In some embodiments, LD is -OCH2-*. In some embodiments, LD is -CH2O-*. [00122] In some embodiments, LD is –C1–4 alkyl-, –C1-3 alkyl-, –C2-3 alkyl-, or –C1-2 alkyl-. In so me embodiments, LD is –C1–4 alkyl-. In some embodiments, LD is –C1-3 alkyl-. In some embodiments, LD is–C2-3 alkyl-. In some embodiments, LD is –C1-2 alkyl-. [00123] In some embodiments, LD is -CH2-, -CH2CH2-, -CH2CH2-O-CH2-*, -CH2-O-CH2-, -CH2-O-CH2CH2-*, or -CH2CH2CH2-, wherein “-*” represents a covalent bond to CyA. In some embodiments, LD is -CH2-. In some embodiments, LD is -CH2CH2-. In some embodiments, LD is - CH2CH2-O-CH2. In some embodiments, LD is -CH2-O-CH2-. In some embodiments, LD is -CH2-O-CH2CH2-. In some embodiments, LD is -CH2CH2CH2-. [00124] In some embodiments, LD is
Figure imgf000073_0001
, ,
Figure imgf000073_0002
[00125] In some embodiments, LD is selected from the groups depicted in the compounds in Table 1. [00126] As defined generally above, RC1 is C1-4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1–4 haloalkyl, C1–4 alkoxy, and C1–4 haloalkoxy. [00127] In some embodiments, RC1 is C1-4 aliphatic substituted with 0-4 instances of a group independently selected from halogen, C1–4 haloalkyl, C1–4 alkoxy, and C1–4 haloalkoxy. In some embodiments, RC1 is methyl. In some embodiments, RC1 is ethyl. [00128] In some embodiments, RC1 is C1–4 haloalkyl. In some embodiments, RC1 is -CF3. In some embodiments, RC1 is -CHF2. In some embodiments, RC1 is -CH2F. In some embodiments, RC1 is -CClF2. [00129] As defined generally above, each instance of R1 (e.g., the R1 group of RA, the R1 group of RB) is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. In some embodiments, R1 is oxo. In some embodiments, each R1 is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. [00130] In some embodiments, R1 is halogen, -CN, or -NO2. In some embodiments, R1 is -OR, -SR, or -NR2. In some embodiments, R1 is -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, or -C(O)N(R)OR. In some embodiments, R1 is -S(O)2R, -S(O)2N(H)R, -S(O)R, -S(O)N(H)R, -C(O)R, -C(O)OR, -C(O)N(H)R, -C(NH)N(H)R, or -C(O)N(H)OR. In some embodiments, R1 is -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. In some embodiments, R1 is -OC(O)R, -OC(O)N(H)R, -N(H)C(O)OR, -N(H)C(O)R, -N(H)C(NH)R, -N(H)C(O)NR2, -N(H)C(NH)NR2, -N(H)S(O)2NR2, -N(H)S(O)R, or –N(H)S(O)2R. In some embodiments, RA is halogen. In some embodiments, RB is halogen. In some embodiments, RB is -C≡N. In some embodiments, RC is -S(O)2R. In some embodiments, RC is -S(O)2CH3. In some embodiments, RC is –OR. In some embodiments, RC is –OCH3. In some embodiments, RC is oxo. In some embodiments, RC is -N(R)C(O)R. In some such embodiments, RC is -N(H)C(O)R. In some embodiments, RC is -C≡N. [00131] As defined generally above, each instance of R2 (e.g., the R2 group of RA, the R2 group of RB, or the R2 group of RC) is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is C1-7 aliphatic. In some embodiments, R2 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is phenyl. In some embodiments, R2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00132] In some embodiments, RA is C1-7 aliphatic. In some such embodiments, RA is –CH3. In some embodiments, RA is -C(CH3)3. [00133] In some embodiments, RB is C1-7 aliphatic. In some such embodiments, RB is -CH3. In some embodiments, RB is selected from –CH3, -CH2CH3, -CH(CH3)2,
Figure imgf000075_0001
In some embodiments, RB is C1-7 aliphatic substituted with R3. In some embodiments, RB is C1-7 aliphatic substituted with R3, wherein R3 is –OR. In some embodiments, RB is C1-2 aliphatic substituted with R3, wherein R3 is –OR. In some embodiments, RB is –CH2OH. In some embodiments, RB is oxo. In some embodiments, RB is –OR, wherein R is C1–6 aliphatic. In some embodiments, RB is –OCH3. [00134] In some embodiments, RC is C1-7 aliphatic. In some such embodiments, RC is -CH3 or – C(CH3)3. In some embodiments, RC–CH2C(CH3)3. In some embodiments, RC is C1-7 aliphatic substituted with R3. In some embodiments, RC is C1-7 aliphatic substituted with R3, wherein R3 is –OR. In some embodiments, RC is C1-2 aliphatic substituted with R3, wherein R3 is –OR. In some embodiments, RC is –CH2OCH3. In some embodiments, RC is
Figure imgf000076_0001
. In some embodiments, RC is -N(H)C(O)CH3. In some embodiments, RC is -C(O)OR. In some embodiments, RC is -C(O)OR, wherein R is C1–6 aliphatic. In some embodiments, RC is -C(O)OCH2CH3. In some embodiments, RC is C1-7 aliphatic substituted with R3, wherein R3 is halogen. In some embodiments, RC is C1-7 aliphatic substituted with R3, wherein R3 is fluorine. In some embodiments, RC is -CF3. In some embodiments, RC is oxo. In some embodiments, RC is –OR substituted with R3. In some embodiments, RC is –OR substituted with R3, wherein R is C1-6 aliphatic and R3 is –OR. In some embodiments, RC is -OCH2CH2OH. In some embodiments, RC is C1-7 aliphatic substituted with R3, wherein R3 is -OR. In some embodiments, RC is C1-7 aliphatic substituted with R3, wherein R3 is -OR. In some embodiments, RC is C1-7 aliphatic substituted with R3, wherein R3 is -OR and R is C1-6 aliphatic, optionally substituted with halogen. [00135] In some embodiments, RC is -OCH2CF3. In some embodiments, RC is -OCH2CHF2. In some embodiments, RC is -CH2OCF3. In some embodiments, RC is -CH2OCHF2. [00136] As defined generally above, each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is oxo. In some embodiments, R3 is halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is halogen, -CN, or -NO2. In some embodiments, R3 is -OR, -SR, or -NR2. In some embodiments, R3 is -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, or -C(O)N(R)OR. In some embodiments, R3 is -S(O)2R, -S(O)2N(H)R, -S(O)R, -S(O)N(H)R, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)N(H)R, -C(NH)NR2, or -C(O)N(H)OR. In some embodiments, R3 is OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. In some embodiments, R3 is -OC(O)R, -OC(O)N(H)R, -N(H)C(O)OR, -N(H)C(O)R, -N(H)C(NH)R, -N(H)C(O)NR2, -N(H)C(NH)NR2, -N(H)S(O)2NR2, -N(H)S(O)R, or –N(H)S(O)2R. In some embodiments, R3 is an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is optionally substituted C1-6 aliphatic. In some embodiments, R3 is optionally substituted phenyl. In some embodiments, R3 is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00137] As defined generally above, CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q. In some embodiments, CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring. In some embodiments, CyC is a saturated or partially unsaturated 3-7 membered monocyclic carbocyclic ring. In some embodiments, CyC is cyclopropyl. [00138] In some embodiments, CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 6-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q. In some embodiments, CyC is a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyC is phenyl. In some embodiments, CyC is a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyC is a 6-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00139] In some embodiments, CyC is a 5-6 membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, CyC is a 5-membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, CyC is a 5-membered heteroaryl ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, CyC is a 5-membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen or sulfur. In some embodiments, CyC is
Figure imgf000078_0001
In some embodiments,
Figure imgf000078_0002
Figure imgf000079_0002
. [00140] In some embodiments, CyC is a 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, CyC is pyridyl. In some embodiments, CyC is pyrimidinyl. In some embodiments, CyC is pyridazinyl. In some embodiments, CyC is
Figure imgf000079_0001
. In some embodiments, CyC is
Figure imgf000079_0004
Figure imgf000079_0003
[00141] In some embodiments, CyC is a 9-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyC is a 9-10 membered heteroaryl having 1-3 heteroatoms indepen dently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyC is a 9-10 membered heteroaryl having 2-4 nitrogen atoms. In some embodiments, CyC is C
Figure imgf000079_0005
In some embodiments, Cy is
Figure imgf000079_0006
In some
Figure imgf000080_0001
[00142] As defined generally above, RD is RD’,
Figure imgf000081_0001
, , wherein LD, RD1, RD2, and RD3 are as defined herein. In some embodiments, RD is
Figure imgf000081_0002
. In some embodiments RD is
Figure imgf000081_0003
. [00143] In some embodiments, RD is
Figure imgf000081_0004
. In some embodiments RD is In some embodime D
Figure imgf000081_0005
nts, R is
Figure imgf000081_0006
[00144] As generally defined above, RD’ is a group capable of being cleaved after administration to a subject. In some embodiments, RD’ comprises a phosphate group. In some embodiments, RD’ comprises an amino acid group. In some embodiments, RD’ comprises a disulfide group. In some embodiments, RD’ comprises a glucuronide group. [00145] As defined generally above, each of RD1 and RD2 is independently hydrogen, R1, or R2, wherein RD1 is substituted with qD1 instances of R3, and RD2 is substituted with qD2 instances of R3; or an instance of RD1 and an instance of RD2 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with qDD instances of R3. [00146] In some embodiments, RD1 is hydrogen, R1, or R2, wherein RD1 is substituted with qD1 instances of R3. In some embodiments, RD1 is hydrogen. In some embodiments, RD1 is R1, wherein RD1 is substituted with qD1 instances of R3. In some embodiments, RD1 is R2 , wherein RD1 is substituted with qD1 instances of R3 . [00147] In some embodiments, RD1 is C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD1 is C1-7 aliphatic. In some embodiments, RD1 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD1 is phenyl. In some embodiments, RD1 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD1 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD1 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, RD1 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD1 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00148] In some embodiments, RD1 is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. In some embodiments, RD1 is oxo. In some embodiments, each RD1 is halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. [00149] In some embodiments, RD1 is halogen, -CN, or -NO2. In some embodiments, RD1 is -OR, -SR, or -NR2. In some embodiments, RD1 is -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, or -C(O)N(R)OR. In some embodiments, RD1 is -S(O)2R, -S(O)2N(H)R, -S(O)R, -S(O)N(H)R, -C(O)R, -C(O)OR, -C(O)N(H)R, -C(NH)N(H)R, or -C(O)N(H)OR. In some embodiments, RD1 is -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. In some embodiments, RD1 is -OC(O)R, -OC(O)N(H)R, -N(H)C(O)OR, -N(H)C(O)R, -N(H)C(NH)R, -N(H)C(O)NR2, -N(H)C(NH)NR2, -N(H)S(O)2NR2, -N(H)S(O)R, or –N(H)S(O)2R. [00150] In some embodiments, RD1 is C1-7 aliphatic. In some embodiments, RD1 is C1-4 aliphatic. In some embodiments, RD1 is methyl. In some embodiments, RD1 is ethyl. In some embodiments, RD1 is n-propyl. In some embodiments, RD1 is isopropyl. In some embodiments, RD1 is n-butyl. In some embodiments, RD1 is s-butyl. In some embodiments, RD1 is t-butyl. [00151] In some embodiments, RD2 is hydrogen, R1, or R2 , wherein RD2 is substituted with qD2 instances of R3. In some embodiments, RD2 is hydrogen. In some embodiments, RD2 is R1 , wherein RD2 is substituted with qD2 instances of R3. In some embodiments, RD1 is R2 , wherein RD2 is substituted with qD2 instances of R3. [00152] In some embodiments, RD2 is C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD2 is C1-7 aliphatic. In some embodiments, RD2 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD2 is phenyl. In some embodiments, RD2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD2 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, RD2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00153] In some embodiments, RD2 is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. In some embodiments, RD2 is oxo. In some embodiments, each RD2 is halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. [00154] In some embodiments, RD2 is halogen, -CN, or -NO2. In some embodiments, RD2 is -OR, -SR, or -NR2. In some embodiments, RD2 is -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, or -C(O)N(R)OR. In some embodiments, RD2 is -S(O)2R, -S(O)2N(H)R, -S(O)R, -S(O)N(H)R, -C(O)R, -C(O)OR, -C(O)N(H)R, -C(NH)N(H)R, or -C(O)N(H)OR. In some embodiments, RD2 is -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. In some embodiments, RD2 is -OC(O)R, -OC(O)N(H)R, -N(H)C(O)OR, -N(H)C(O)R, -N(H)C(NH)R, -N(H)C(O)NR2, -N(H)C(NH)NR2, -N(H)S(O)2NR2, -N(H)S(O)R, or –N(H)S(O)2R. [00155] In some embodiments, RD2 is C1-7 aliphatic. In some embodiments, RD2 is C1–4 aliphatic. In some embodiments, RD2 is methyl. In some embodiments, RD2 is ethyl. In some embodiments, RD2 is n-propyl. In some embodiments, RD2 is isopropyl. In some embodiments, RD2 is n-butyl. In some embodiments, RD2 is s-butyl. In some embodiments, RD2 is t-butyl. [00156] In some embodiments, an instance of RD1 and an instance of RD2 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with qDD instances of R3. In some embodiments, an instance of RD1 and an instance of RD2 are taken together with their intervening atoms to form a 4-membered saturated ring substituted with qDD instances of R3. In some embodiments, an instance of RD1 and an instance of RD2 are taken together with their intervening atoms to form a 5-membered saturated ring substituted with qDD instances of R3. In some embodiments, an instance of RD1 and an instance of RD2 are taken together with their intervening atoms to form a 5-6 membered saturated ring substituted with qDD instances of R3. In some embodiments, an instance of RD1 and an instance of RD2 are taken together with their intervening atoms to form a 6-membered saturated ring substituted with qDD instances of R3. In some embodiments, an instance of RD1 and an instance of RD2 are taken together with their intervening atoms to form a 7-membered saturated ring substituted with qDD instances of R3. In some embodiments, an instance of RD1 and an instance of RD2 are taken together with their intervening atoms to form an 8-membered saturated ring substituted with qDD instances of R3. [00157] As defined generally above, RD3 is hydrogen, R1, or R2, wherein RD3 is substituted by qD3 instances of R3. In some embodiments, RD3 is hydrogen. In some embodiments, RD3 is R1, wherein RD3 is substituted by qD3 instances of R3 . In some embodiments, RD3 is R2, wherein RD3 is substituted by qD3 instances of R3. [00158] In some embodiments, RD3 is C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD3 is C1-7 aliphatic. In some embodiments, RD3 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD3 is phenyl. In some embodiments, RD3 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD3 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD3 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, RD3 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RD3 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00159] In some embodiments, RD3 is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. In some embodiments, RD3 is oxo. In some embodiments, each RD3 is halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. [00160] In some embodiments, RD3 is halogen, -CN, or -NO2. In some embodiments, RD3 is -OR, -SR, or -NR2. In some embodiments, RD3 is -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, or -C(O)N(R)OR. In some embodiments, RD3 is -S(O)2R, -S(O)2N(H)R, -S(O)R, -S(O)N(H)R, -C(O)R, -C(O)OR, -C(O)N(H)R, -C(NH)N(H)R, or -C(O)N(H)OR. In some embodiments, RD3 is -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R. In some embodiments, RD3 is -OC(O)R, -OC(O)N(H)R, -N(H)C(O)OR, -N(H)C(O)R, -N(H)C(NH)R, -N(H)C(O)NR2, -N(H)C(NH)NR2, -N(H)S(O)2NR2, -N(H)S(O)R, or –N(H)S(O)2R. [00161] In some embodiments, RD3 is C1-7 aliphatic. In some embodiments, RD3 is C1-4 aliphatic. In some embodiments, RD3 is methyl. In some embodiments, RD3 is ethyl. In some embodiments, RD3 is n-propyl. In some embodiments, RD3 is isopropyl. In some embodiments, RD3 is n-butyl. In some embodiments, RD3 is s-butyl. In some embodiments, RD3 is t-butyl. [00162] As defined generally above, each R is independently hydrogen, or an optionally substituted group selected from C1–6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from C1-6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is an optionally substituted saturated or partially unsaturated 3-7 membered carbocyclic ring. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00163] As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0 or 1. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 2 or 3. In some embodiments, m is 2, 3, or 4. In some embodiments, m is 3 or 4. In some embodiments, m is selected from the values represented in the compounds in Table 1. [00164] As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 2 or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 3 or 4. In some embodiments, n is selected from the values represented in the compounds in Table 1. [00165] As defined generally above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 0 or 1. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. In some embodiments, p is 2, 3, or 4. In some embodiments, p is 3 or 4. In some embodiments, p is selected from the values represented in the compounds in Table 1. [00166] As defined generally above, qA is 0, 1, 2, 3, or 4. In some embodiments, qA is 0. In some embodiments, qA is 1. In some embodiments, qA is 2. In some embodiments, qA is 3. In some embodiments, qA is 4. In some embodiments, qA is 0 or 1. In some embodiments, qA is 0, 1, or 2. In some embodiments, qA is 0, 1, 2, or 3. In some embodiments, qA is 1 or 2. In some embodiments, qA is 1, 2, or 3. In some embodiments, qA is 1, 2, 3, or 4. In some embodiments, qA is 2 or 3. In some embodiments, qA is 2, 3, or 4. In some embodiments, qA is 3 or 4. In some embodiments, qA is selected from the values represented in the compounds in Table 1. [00167] As defined generally above, qB is 0, 1, 2, 3, or 4. In some embodiments, qB is 0. In some embodiments, qB is 1. In some embodiments, qB is 2. In some embodiments, qB is 3. In some embodiments, qB is 4. In some embodiments, qB is 0 or 1. In some embodiments, qB is 0, 1, or 2. In some embodiments, qB is 0, 1, 2, or 3. In some embodiments, qB is 1 or 2. In some embodiments, qB is 1, 2, or 3. In some embodiments, qB is 1, 2, 3, or 4. In some embodiments, qB is 2 or 3. In some embodiments, qB is 2, 3, or 4. In some embodiments, qB is 3 or 4. In some embodiments, qB is selected from the values represented in the compounds in Table 1. [00168] As defined generally above, qD1 is 0, 1, 2, 3, or 4. In some embodiments, qD1 is 0. In some embodiments, qD1 is 1. In some embodiments, qD1 is 2. In some embodiments, qD1 is 3. In some embodiments, qD1 is 4. In some embodiments, qD1 is 0 or 1. In some embodiments, qD1 is 0, 1, or 2. In some embodiments, qD1 is 0, 1, 2, or 3. In some embodiments, qD1 is 1 or 2. In some embodiments, qD1 is 1, 2, or 3. In some embodiments, qD1 is 1, 2, 3, or 4. In some embodiments, qD1 is 2 or 3. In some embodiments, qD1 is 2, 3, or 4. In some embodiments, qD1 is 3 or 4. In some embodiments, qD1 is selected from the values represented in the compounds in Table 1. [00169] As defined generally above, qD2 is 0, 1, 2, 3, or 4. In some embodiments, qD2 is 0. In some embodiments, qD2 is 1. In some embodiments, qD2 is 2. In some embodiments, qD2 is 3. In some embodiments, qD2 is 4. In some embodiments, qD2 is 0 or 1. In some embodiments, qD2 is 0, 1, or 2. In some embodiments, qD2 is 0, 1, 2, or 3. In some embodiments, qD2 is 1 or 2. In some embodiments, qD2 is 1, 2, or 3. In some embodiments, qD2 is 1, 2, 3, or 4. In some embodiments, qD2 is 2 or 3. In some embodiments, qD2 is 2, 3, or 4. In some embodiments, qD2 is 3 or 4. In some embodiments, qD2 is selected from the values represented in the compounds in Table 1. [00170] As defined generally above, qD3 is 0, 1, 2, 3, or 4. In some embodiments, qD3 is 0. In some embodiments, qD3 is 1. In some embodiments, qD3 is 2. In some embodiments, qD3 is 3. In some embodiments, qD3 is 4. In some embodiments, qD3 is 0 or 1. In some embodiments, qD3 is 0, 1, or 2. In some embodiments, qD3 is 0, 1, 2, or 3. In some embodiments, qD3 is 1 or 2. In some embodiments, qD3 is 1, 2, or 3. In some embodiments, qD3 is 1, 2, 3, or 4. In some embodiments, qD3 is 2 or 3. In some embodiments, qD3 is 2, 3, or 4. In some embodiments, qD3 is 3 or 4. In some embodiments, qD3 is selected from the values represented in the compounds in Table 1. [00171] As defined generally above, qDD is 0, 1, 2, 3, or 4. In some embodiments, qDD is 0. In some embodiments, qDD is 1. In some embodiments, qDD is 2. In some embodiments, qDD is 3. In some embodiments, qDD is 4. In some embodiments, qDD is 0 or 1. In some embodiments, qDD is 0, 1, or 2. In some embodiments, qDD is 0, 1, 2, or 3. In some embodiments, qDD is 1 or 2. In some embodiments, qDD is 1, 2, or 3. In some embodiments, qDD is 1, 2, 3, or 4. In some embodiments, qDD is 2 or 3. In some embodiments, qDD is 2, 3, or 4. In some embodiments, qDD is 3 or 4. In some embodiments, qDD is selected from the values represented in the compounds in Table 1. [00172] As defined generally above, qP is 0, 1, 2, 3, or 4. In some embodiments, qP is 0. In some embodiments, qP is 1. In some embodiments, qP is 2. In some embodiments, qP is 3. In some embodiments, qP is 4. In some embodiments, qP is 0 or 1. In some embodiments, qP is 0, 1, or 2. In some embodiments, qP is 0, 1, 2, or 3. In some embodiments, qP is 1 or 2. In some embodiments, qP is 1, 2, or 3. In some embodiments, qP is 1, 2, 3, or 4. In some embodiments, qP is 2 or 3. In some embodiments, qP is 2, 3, or 4. In some embodiments, qP is 3 or 4. In some embodiments, qP is selected from the values represented in the compounds in Table 1. [00173] As defined generally above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0 or 1. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 1 or 2. In some embodiments, r is 1, 2, or 3. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, r is 2 or 3. In some embodiments, r is 2, 3, or 4. In some embodiments, r is 3 or 4. In some embodiments, r is selected from the values represented in the compounds in Table 1. [00174] As defined generally above, t is 0, 1, 2, 3, or 4. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 0 or 1. In some embodiments, t is 0, 1, or 2. In some embodiments, t is 0, 1, 2, or 3. In some embodiments, t is 1 or 2. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1, 2, 3, or 4. In some embodiments, t is 2 or 3. In some embodiments, t is 2, 3, or 4. In some embodiments, t is 3 or 4. In some embodiments, t is selected from the values represented in the compounds in Table 1. [00175] Examples of compounds described herein include those listed in the Tables and exemplification herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure comprises a compound selected from those depicted in Table 1, below, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1, below, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1, below. Table 1. Representative Compounds with Bioactivity Data.
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000341_0001
Figure imgf000342_0001
Figure imgf000343_0001
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000358_0001
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
Figure imgf000362_0001
Figure imgf000363_0001
Figure imgf000364_0001
Figure imgf000365_0001
Figure imgf000366_0001
Figure imgf000367_0001
Figure imgf000368_0001
Figure imgf000369_0001
Figure imgf000370_0001
Figure imgf000371_0001
Figure imgf000372_0001
Figure imgf000373_0001
Figure imgf000374_0001
Figure imgf000375_0001
Figure imgf000376_0001
Figure imgf000377_0001
Figure imgf000378_0001
Figure imgf000379_0001
Figure imgf000380_0001
Figure imgf000381_0001
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000390_0001
Figure imgf000391_0001
Figure imgf000392_0001
Figure imgf000393_0001
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Figure imgf000406_0001
Figure imgf000407_0001
Figure imgf000408_0001
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
Figure imgf000415_0001
Figure imgf000416_0001
Figure imgf000417_0001
Figure imgf000418_0001
Figure imgf000419_0001
Figure imgf000420_0001
Figure imgf000421_0001
Figure imgf000422_0001
Figure imgf000423_0001
Figure imgf000424_0001
Figure imgf000425_0001
Figure imgf000426_0001
Figure imgf000427_0001
Figure imgf000428_0001
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0001
Figure imgf000433_0001
Figure imgf000434_0001
Figure imgf000435_0001
Figure imgf000436_0001
Figure imgf000437_0001
Figure imgf000438_0001
Figure imgf000439_0001
Figure imgf000440_0001
Figure imgf000441_0001
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000453_0001
Figure imgf000454_0001
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Figure imgf000463_0001
Figure imgf000464_0001
Figure imgf000465_0001
Figure imgf000466_0001
Figure imgf000467_0001
Figure imgf000468_0001
Figure imgf000469_0001
Figure imgf000470_0001
Figure imgf000471_0001
Figure imgf000472_0001
Figure imgf000473_0001
Figure imgf000474_0001
Figure imgf000475_0001
Figure imgf000476_0001
Figure imgf000477_0001
Figure imgf000478_0001
Figure imgf000479_0001
Figure imgf000480_0001
Figure imgf000481_0001
Figure imgf000482_0001
Figure imgf000483_0001
Figure imgf000484_0001
Figure imgf000485_0001
Figure imgf000486_0001
Figure imgf000487_0001
Figure imgf000488_0001
Figure imgf000489_0001
Figure imgf000490_0001
Figure imgf000491_0001
Figure imgf000492_0001
Figure imgf000493_0001
Figure imgf000494_0001
Figure imgf000495_0001
Figure imgf000496_0001
Figure imgf000497_0001
Figure imgf000498_0001
Figure imgf000499_0001
Figure imgf000500_0001
Figure imgf000501_0001
Figure imgf000502_0001
Figure imgf000503_0001
Figure imgf000504_0001
Figure imgf000505_0001
Figure imgf000506_0001
Figure imgf000507_0001
Figure imgf000508_0001
Figure imgf000509_0001
Figure imgf000510_0001
Figure imgf000511_0001
Figure imgf000512_0001
Figure imgf000513_0001
Figure imgf000514_0001
Figure imgf000515_0001
Figure imgf000516_0001
Figure imgf000517_0001
Figure imgf000518_0001
Figure imgf000519_0001
Figure imgf000520_0001
Figure imgf000521_0001
Figure imgf000522_0001
Figure imgf000523_0001
Figure imgf000524_0001
Figure imgf000525_0001
Figure imgf000526_0001
Figure imgf000527_0001
Figure imgf000528_0001
Figure imgf000529_0001
Figure imgf000530_0001
Figure imgf000531_0001
Figure imgf000532_0001
Figure imgf000533_0001
Figure imgf000534_0001
Figure imgf000535_0001
Figure imgf000536_0001
Figure imgf000537_0001
Figure imgf000538_0001
Figure imgf000539_0001
Figure imgf000540_0001
Figure imgf000541_0001
Figure imgf000542_0001
Figure imgf000543_0001
Figure imgf000544_0001
Figure imgf000545_0001
Figure imgf000546_0001
Figure imgf000547_0001
Figure imgf000548_0001
Figure imgf000549_0001
Figure imgf000550_0001
Figure imgf000551_0001
Figure imgf000552_0001
Figure imgf000553_0001
Figure imgf000554_0001
Figure imgf000555_0001
Figure imgf000556_0001
Figure imgf000557_0001
Figure imgf000558_0001
Figure imgf000559_0001
Figure imgf000560_0001
Figure imgf000561_0001
Figure imgf000562_0001
Figure imgf000563_0001
Figure imgf000564_0001
Figure imgf000565_0001
Figure imgf000566_0001
Figure imgf000567_0001
Figure imgf000568_0001
Figure imgf000569_0001
Figure imgf000570_0001
Figure imgf000571_0001
Figure imgf000572_0001
[00176] In chemical structures in Table 1, above, when a stereocenter is depicted with a dashed or wedged bond and labeled “abs” (or unlabeled), the compound is essentially a single isomer at that stereocenter (rather than an equimolar mixture), and the absolute stereochemistry is as shown in the chemical structure. (See, for example, the structure of Example 1.) When a stereocenter is depicted with a dashed or wedged bond and also labeled “or1” or “or2,” the compound is a single isomer at that stereocenter, but the absolute stereochemistry at that stereocenter has not been determined. (See, for example, the structure of Example 203.) When a stereocenter is depicted with a dashed or wedged bond and also labeled “and1” or “&1”, the compound is a mixture of two isomers at that stereocenter: the structure as drawn, and the isomer in which that stereogenic center has the opposite configuration. [00177] Certain compounds depicted in Table 1, above, exist in solution at room temperature as non-interconverting atropisomers across a biaryl bond. When one of the atoms of a biaryl bond is labeled as “or1”, this signifies that the compound exists in solution at room termperature as non- interconverting atropisomers, and the compound is essentially a single atropisomer (rather than an equimolar mixture). [00178] In some embodiments, the present disclosureprovides a compound in Table 1, above, wherein the compound is denoted as having a Biochemical CDK2 Caliper IC50 of “A”. In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Biochemical CDK2 Caliper IC50 of “A” or “B”. In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Biochemical CDK2 Caliper IC50 of “A” or “B” or “C”. [00179] In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Cell nanoBRET IC50 of “A”. In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Cell nanoBRET IC50 of “A” or “B”. In some embodiments, the present disclosure provides a compound in Table 1, above, wherein the compound is denoted as having a Cell nanoBRET IC50 of “A” or “B” or “C”. 4. General Methods of Providing the Present Compounds [00180] The compounds described herein may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein. [00181] In some embodiments, the present disclosure provides methods of preparing a compound of formula I:
Figure imgf000573_0001
or a salt thereof, wherein CyA, CyB, CyC, Q, and P are as defined and described above and herein, comprising a step of: reacting a compound of formula XXVIII:
Figure imgf000574_0001
or a salt thereof, wherein CyA, CyB, CyC, Q, P, and RD are as defined and described above and herein, under suitable reaction conditions to provide the compound of formula I, or a salt thereof. [00182] In some embodiments, provided methods further comprise administering a compound of formula XXVIII, or a salt thereof, to a subject or patient as defined and described herein. In some embodiments, provided methods comprise reacting the compound of formula XXVIII, or a salt thereof, after administration to a subject or patient as defined and described herein. In some embodiments, provided methods comprise reacting the compound of formula XXVIII, or a salt thereof, within a subject or patient as defined and described herein. In some embodiments, provided methods comprise reacting a compound of formula XXVIII, or a salt thereof, in vivo. 5. Uses, Formulation, and Administration Pharmaceutically Acceptable Compositions [00183] According to another embodiment, the present disclosure provides a composition comprising a compound described herein, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein, and a pharmaceutically acceptable carrier. The amount of compound in compositions described herein is such that is effective to measurably inhibit a CDK2 protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions described herein is such that it is effective to measurably inhibit a CDK2 protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient. [00184] The terms “subject” and “patient,” as used herein, means an animal (i.e., a member of the kingdom animal), preferably a mammal, and most preferably a human. In some embodiments, the subject is a human, mouse, rat, cat, monkey, dog, horse, or pig. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, rat, cat, monkey, dog, horse, or pig. [00185] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. [00186] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound described herein that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound described herein or an inhibitorily active metabolite or residue thereof. [00187] As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a CDK2 protein kinase, or a mutant thereof. [00188] Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.
[00189] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
[00190] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
[00191] Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[00192] Alternatively, pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore will melt in the rectum or vagina to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[00193] Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
[00194] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
[00195] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
[00196] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. [00197] Pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00198] Preferably, pharmaceutically acceptable compositions described herein are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions described herein are administered with food. [00199] The amount of compounds described herein that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the patient treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. [00200] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the composition. [00201] The precise dose to be employed in the compositions will also depend on the route of administration and should be decided according to the judgment of the practitioner and each subject’s circumstances. In specific embodiments of the disclosure, suitable dose ranges for oral administration of the compounds of the disclosure are generally about 1 mg/day to about 1000 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 800 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 500 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 250 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 100 mg/day. In some embodiments, the oral dose is about 5 mg/day to about 50 mg/day. In some embodiments, the oral dose is about 5 mg/day. In some embodiments, the oral dose is about 10 mg/day. In some embodiments, the oral dose is about 20 mg/day. In some embodiments, the oral dose is about 30 mg/day. In some embodiments, the oral dose is about 40 mg/day. In some embodiments, the oral dose is about 50 mg/day. In some embodiments, the oral dose is about 60 mg/day. In some embodiments, the oral dose is about 70 mg/day. In some embodiments, the oral dose is about 100 mg/day. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit.
[00202] In some embodiments, pharmaceutically acceptable compositions contain a provided compound and/or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 90 wt%, about 0.01 to about 80 wt%, about 0.01 to about 70 wt%, about 0.01 to about 60 wt%, about 0.01 to about 50 wt%, about 0.01 to about 40 wt%, about 0.01 to about 30 wt%, about 0.01 to about 20 wt%, about 0.01 to about 2.0 wt%, about 0.01 to about 1 wt%, about 0.05 to about 0.5 wt%, about 1 to about 30 wt%, or about 1 to about 20 wt%. The composition can be formulated as a solution, suspension, ointment, or a capsule, and the like. The pharmaceutical composition can be prepared as an aqueous solution and can contain additional components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscositymodifying ingredients and the like.
[00203] Pharmaceutically acceptable carriers are well-known to those skilled in the art, and include, e.g., adjuvants, diluents, excipients, fillers, lubricants and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient.
[00204] Examples of pharmaceutically acceptable carriers may include, e.g., water or saline solution, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids, or alcohols. Non-limiting examples of oils as pharmaceutical carriers include oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in e.g., Remington’s: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)) (each of which hereby incorporated by reference in its entirety). [00205] The pharmaceutically acceptable carriers employed herein may be selected from various organic or inorganic materials that are used as materials for pharmaceutical formulations and which are incorporated as analgesic agents, buffers, binders, disintegrants, diluents, emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and viscosity-increasing agents. Pharmaceutical additives, such as antioxidants, aromatics, colorants, flavor-improving agents, preservatives, and sweeteners, may also be added. Examples of acceptable pharmaceutical carriers include carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc and water, among others. In some embodiments, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. [00206] Surfactants such as, e.g., detergents, are also suitable for use in the formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others, anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sufate and sodium cetyl sulfate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids, in particular those derived from coconut oil, cationic surfactants, such as water-soluble quaternary ammonium salts of formula N+R'R''R'''R''''Y-, in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals and Y- is an anion of a strong acid, such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants which can be used, amine salts of formula N+R'R''R''', in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants which can be used, non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, in particular Polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaine. [00207] Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. The present compositions, if desired, may also contain wetting or emulsifying agents, or pH buffering agents. [00208] Tablets and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which are known in the art. Examples of such include carbohydrates such as lactose or sucrose, dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffering agents, disintegrants, and colorants. Orally administered compositions may contain one or more optional agents such as, e.g., sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preservative agents, to provide a pharmaceutically palatable preparation. Uses of Compounds and Pharmaceutically Acceptable Compositions [00209] Compounds and compositions described herein are generally useful for the inhibition of a kinase or a mutant thereof. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a cyclin dependent kinase (CDK). In some embodiments, the kinase inhibited by the compounds and compositions described herein is one or more of CDK1, CDK2, CDK4, and CDK6. In some embodiments, the kinase inhibited by the compounds and compositions described herein is CDK2. [00210] Compounds or compositions of the disclosure can be useful in applications that benefit from inhibition of CDK2 enzymes. For example, CDK2 inhibitors described herein are useful for the treatment of proliferative diseases generally. [00211] CDK2 is known to be an factor in tumorigenesis and proliferation in many cancer types including lung cancer, liver cancer, colon cancer and breast cancer (Opyrchal, Int J Oncol 2014; Shi, PLoS One 2015; Lim, Cancer Prev Res 2014). There is evidence showing that CDK2 is functionally linked with hyper proliferation in multiple cancer cells and is a potential therapeutic target for cancer therapy (Chohan, Curr Med Chem 2015). [00212] CDK2 plays a role for the malignant transformation of breast epithelial cells. Suppression of CDK2 activity can effectively inhibit the proliferation of human breast cancer cells (Ali, Cancer Res 2009). Active CDK2 in the form of a cyclin D1/CDK2 fusion protein induces tumors that contain an invasive component that exhibits multiple features in common with human basal-like tumors and tumor-derived cell lines (Corsino, Neoplasia 2008). Cyclin D1/CDK2 complexes were detected in human breast cancer cell lines (Sweeney, Oncogene 1998), and the levels of these complexes correlated well with the degree of cyclin D1 overexpression. [00213] The role of cyclin E and its associated kinase CDK2 in ovarian cancer has been investigated by screening primary, metastatic, recurrent and benign ovarian tumors. Using gene amplification, Cyclin E was shown to be amplified in 21% and CDK2 in 6.4% of the cases analyzed. Additionally, Cyclin E RNA was overexpressed in 29.5% and CDK2 in 6.5% of ovarian tumors tested. Cyclin E and CDK2 were overexpressed mostly in primary ovarian cancers (32% and 10%, respectively) compared to metastatic and recurrent diseases (Marone, Int J Cancer 1998). [00214] CDK2 expression has been found to be significantly elevated in glioma tumor especially in Glioblastoma Multiforme (GBM) and was functionally required for GBM cell proliferation and tumorigenesis (Wang, Transl Oncol 2016). CDK2 expression was identified to be significantly enriched in GBM tumors and functionally required for tumor proliferation both in vitro and in vivo. Additionally, high CDK2 expression was associated to poor prognosis in GBM patients. Radio resistance is a major factor of poor clinical prognosis and tumor recurrence in GBM patients. CDK2 was found to be one of the most up-regulated kinase encoding genes in GBM after radio treatment. CDK2-dependent radio resistance is indispensable for GBM tumorigenesis and recurrence after therapeutic treatment (Id.). [00215] Elevated levels of CDK2 expression have been observed in human cholangiocarcinoma tissues where apoptosis-related protein-1 dependent suppression of CDK2 induced cell cycle arrest and restrained tumor growth (Zheng, Oncol Rep 2016). [00216] CDK2 overexpression in oral squamous cell carcinoma (SCC) may elevate pRB phosphorylation and permit more rapid entry of the cancer cells into S phase. In a clinicopathological survey of oral SCC, incidence of CDK2 expression was high in the poorly differentiated lesions, and was associated with the mode of tumor invasion, lymph node involvement and survival, an indication that change in CDK2 expression is associated with oral cancer progression (Mihara, Jpn J Cancer Res 2001). CDK2 expression was significantly correlated with lymph node involvement, tumor differentiation, mode of tumor invasion, and shorter survival period. Thus, increased expression of CDK2 is a factor in oral cancer progression and a negative predictive marker of the patients' prognosis (Id.). [00217] CDK2 has been found to play a role in cell proliferation of non-small cell lung cancer (Kawana, Am J Pathol 1998). CDK2 has also been found to play a role in cell proliferation of prostate cancer (Flores, Endocrinology 2010). [00218] The activity of a compound described herein as an inhibitor of an CDK kinase, for example, CDK2, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity and/or the subsequent functional consequences, or ATPase activity of activated CDK2, or a mutant thereof. Alternative in vitro assays quantitate the ability of the inhibitor to bind to CDK2. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/CDK2 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with CDK2 bound to known radioligands. Representative in vitro and in vivo assays useful in assaying an CDK2 inhibitor include those described and disclosed in the patent and scientific publications described herein. Detailed conditions for assaying a compound described herein as an inhibitor of CDK2, or a mutant thereof, are set forth in the Examples below. Treatment of Disorders [00219] Provided compounds are inhibitors of CDK2 and are therefore useful for treating one or more disorders associated with activity of CDK2 or mutants thereof. Thus, in certain embodiments, the present disclosure provides a method of treating an CDK2-mediated disorder in a subject comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing, to a subject in need thereof. In certain embodiments, the present disclosure provides a method of treating an CDK2-mediated disorder in a subject comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. [00220] As used herein, the term “CDK2-mediated” disorders, diseases, and/or conditions means any disease or other deleterious condition in which CDK2 or a mutant thereof is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which CDK2, or a mutant thereof, is known to play a role. Such CDK2-mediated disorders include but are not limited to proliferative disorders (e.g. cancer). [00221] In some embodiments, the present disclosure provides a method for treating one or more disorders, wherein the disorders are selected from proliferative disorders and craniosynostotic syndromes, said method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing. In some embodiments, the present disclosure provides a method for treating one or more disorders, wherein the disorders are selected from proliferative disorders and craniosynostotic syndromes, said method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof. [00222] In some embodiments, the disorder is associated with CDK2 signaling. CDK2 is known to have multiple upstream and downstream signaling pathways and inhibition of CDK2 can be used to treat disorders associated with aberrant signaling within those pathways. In some embodiments, the disorder is associated with cyclin E, cyclin E1, or retinoblastoma protein (RB) signaling. [00223] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said provided compound in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment. [00224] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment. [00225] Another aspect of the disclosure provides a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for use in the treatment of a disorder described herein. Another aspect of the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for the treatment of a disorder described herein. Similarly, the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder described herein. Proliferative Disorders [00226] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the proliferative disorder is ovarian cancer, breast cancer, lung cancer, colorectal cancer, or a combination thereof. In some embodiments, the proliferative disorder is a leukemia. In some embodiments, the proliferative disorder is breast cancer. In some embodiments, the proliferative disorder is a lung cancer. In some embodiments, the proliferative disorder is colorectal cancer. [00227] In some embodiments, the proliferative disorder is breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial carcinoma, non-small cell lung cancer, or bladder cancer. In some embodiments, the proliferative disorder is intrahepatic cholangiocarcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, or ovarian cancer. In some embodiments, the proliferative disorder is gastric cancer, breast cancer, triple negative breast cancer, or rectal cancer. In some embodiments, the proliferative disorder is endometrial carcinoma, non-small cell lung cancer, lung squamous cell carcinoma, gastric cancer, breast cancer, or urothelial cancer. [00228] In some embodiments, the disorder is ovarian cancer, endometrial cancer, gastric cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, stomach cancer, sarcoma cancer, liver cancer, esophageal cancer, laryngeal cancer, multiple myeloma, colorectal cancer, rectal cancer, skin cancer, or pancreatic cancer. In some embodiments, the bladder cancer is urothelial carcinoma. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the lung cancer is lung squamous cell carcinoma or non-small cell lung cancer. In some embodiments, the laryngeal cancer is laryngeal squamous cell carcinoma. In some embodiments, the skin cancer is melanoma. [00229] In some embodiments, the proliferative disorder is associated with a deregulation of CDK2 or cyclin E. In some embodiments, the deregulation of CDK2 is an overexpression of CDK2 or cyclin E. In some embodiments, the deregulation of cyclin E is an overexpression of CDK2 or cyclin E. In some embodiments, the proliferative disorder is associated with a deregulation of CDK2 and cyclin E. In some embodiments, the deregulation of CDK2 and cyclin E is an overexpression of CDK2 and cyclin E. [00230] In some embodiments, the proliferative disorder is associated with one or more activating mutations in CDK2. In some embodiments, the activating mutation in CDK2 is a mutation to one or more of the intracellular kinase domain and the extracellular domain. In some embodiments, the activating mutation in CDK2 is a mutation to the intracellular kinase domain. Routes of Administration and Dosage Forms [00231] The compounds and compositions, according to the methods described herein, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder (e.g. a proliferative disorder or craniosynostotic syndrome). The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
[00232] Pharmaceutically acceptable compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intraci sternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like. In certain embodiments, the compounds described herein may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
[00233] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00234] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00235] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00236] In order to prolong the effect of a compound described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [00237] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [00238] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00239] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00240] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00241] Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Dosage Amounts and Regimens [00242] In accordance with the methods of the present disclosure, the compounds of the disclosure are administered to the subject in a therapeutically effective amount, e.g., to reduce or ameliorate symptoms of the disorder in the subject. This amount is readily determined by the skilled artisan, based upon known procedures, including analysis of titration curves established in vivo and methods and assays disclosed herein. [00243] In some embodiments, the methods comprise administration of a therapeutically effective dosage of the compounds of the disclosure. In some embodiments, the therapeutically effective dosage is at least about 0.0001 mg/kg body weight, at least about 0.001 mg/kg body weight, at least about 0.01 mg/kg body weight, at least about 0.05 mg/kg body weight, at least about 0.1 mg/kg body weight, at least about 0.25 mg/kg body weight, at least about 0.3 mg/kg body weight, at least about 0.5 mg/kg body weight, at least about 0.75 mg/kg body weight, at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, at least about 10 mg/kg body weight, at least about 15 mg/kg body weight, at least about 20 mg/kg body weight, at least about 25 mg/kg body weight, at least about 30 mg/kg body weight, at least about 40 mg/kg body weight, at least about 50 mg/kg body weight, at least about 75 mg/kg body weight, at least about 100 mg/kg body weight, at least about 200 mg/kg body weight, at least about 250 mg/kg body weight, at least about 300 mg/kg body weight, at least about 350 mg/kg body weight, at least about 400 mg/kg body weight, at least about 450 mg/kg body weight, at least about 500 mg/kg body weight, at least about 550 mg/kg body weight, at least about 600 mg/kg body weight, at least about 650 mg/kg body weight, at least about 700 mg/kg body weight, at least about 750 mg/kg body weight, at least about 800 mg/kg body weight, at least about 900 mg/kg body weight, or at least about 1000 mg/kg body weight. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit. [00244] In some embodiments, the therapeutically effective dosage is in the range of about 0.1 mg to about 10 mg/kg body weight, about 0.1 mg to about 6 mg/kg body weight, about 0.1 mg to about 4 mg /kg body weight, or about 0.1 mg to about 2 mg/kg body weight. [00245] In some embodiments the therapeutically effective dosage is in the range of about 1 to 500 mg, about 2 to 150 mg, about 2 to 120 mg, about 2 to 80 mg, about 2 to 40 mg, about 5 to 150 mg, about 5 to 120 mg, about 5 to 80 mg, about 10 to 150 mg, about 10 to 120 mg, about 10 to 80 mg, about 10 to 40 mg, about 20 to 150 mg, about 20 to 120 mg, about 20 to 80 mg, about 20 to 40 mg, about 40 to 150 mg, about 40 to 120 mg or about 40 to 80 mg. [00246] In some embodiments, the methods comprise a single dosage or administration (e.g., as a single injection or deposition). Alternatively, in some embodiments, the methods comprise administration once daily, twice daily, three times daily or four times daily to a subject in need thereof for a period of from about 2 to about 28 days, or from about 7 to about 10 days, or from about 7 to about 15 days, or longer. In some embodiments, the methods comprise chronic administration. In yet other embodiments, the methods comprise administration over the course of several weeks, months, years or decades. In still other embodiments, the methods comprise administration over the course of several weeks. In still other embodiments, the methods comprise administration over the course of several months. In still other embodiments, the methods comprise administration over the course of several years. In still other embodiments, the methods comprise administration over the course of several decades. [00247] The dosage administered can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion. These are all readily determined and may be used by the skilled artisan to adjust or titrate dosages and/or dosing regimens. Inhibition of Protein Kinases [00248] According to one embodiment, the present disclosure relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound described herein, or a composition comprising said compound. [00249] According to another embodiment, the present disclosure relates to a method of inhibiting activity of CDK2, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound described herein, or a composition comprising said compound. In certain embodiments, the present disclosure relates to a method of reversibly inhibiting CDK2, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound described herein, or a composition comprising said compound. [00250] In another embodiment, the present disclosure provides a method of selectively inhibiting CDK2 over one or more of CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, a compound described herein is more than 5-fold selective over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, a compound described herein is more than 10-fold selective over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, a compound described herein is more than 50-fold selective over CDK1, CDK4, CDK5, CDK6, sand CDK9. In some embodiments, a compound described herein is more than 100-fold selective over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, a compound described herein is more than 200- fold selective over CDK1, CDK4, CDK5, CDK6, and CDK9. [00251] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. [00252] Inhibition of activity of CDK2 (or a mutant thereof) in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays. [00253] Another embodiment of the present disclosure relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound described herein, or a composition comprising said compound. [00254] According to another embodiment, the present disclosure relates to a method of inhibiting activity of CDK2, or a mutant thereof, in a patient comprising the step of administering to said patient a compound described herein, or a composition comprising said compound. According to certain embodiments, the present disclosure relates to a method of reversibly inhibiting activity of one or more of CDK2, or a mutant thereof, in a patient comprising the step of administering to said patient a compound described herein, or a composition comprising said compound. [00255] According to another embodiment, the present disclosure provides a method for treating a disorder mediated by CDK2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound described herein or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein. In some embodiments, the present disclosure provides a method for treating a disorder mediated by CDK2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound described herein or a pharmaceutically acceptable composition thereof, wherein the compound reversibly inhibits the CDK2, or a mutant thereof. [00256] According to another embodiment, the present disclosure provides a method of inhibiting signaling activity of CDK2, or a mutant thereof, in a subject, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the present disclosure provides a method of inhibiting CDK2 signaling activity in a subject, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. [00257] In some embodiments, the present disclosure provides a method for treating a disorder mediated by CDK2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound described herein or a pharmaceutically acceptable composition thereof, wherein the compound reversibly inhibits the CDK2, or a mutant thereof. [00258] The compounds described herein can also inhibit CDK2 function through incorporation into agents that catalyze the destruction of CDK2. For example, the compounds can be incorporated into proteolysis targeting chimeras (PROTACs). A PROTAC is a bifunctional molecule, with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. The portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms. Recruitment of CDK2 to the E3 ligase will thus result in the destruction of the CDK2 protein. The variable chain of atoms can include, for example, rings, heteroatoms, and/or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques in the art of organic synthesis. Combination Therapies [00259] Depending upon the particular disorder, condition, or disease, to be treated, additional therapeutic agents, that are normally administered to treat that condition, may be administered in combination with compounds and compositions described herein. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” [00260] Accordingly, in certain embodiments, the method of treatment comprises administering the compound or composition described herein in combination with one or more additional therapeutic agents. In certain other embodiments, the methods of treatment comprise administering the compound or composition described herein as the only therapeutic agent. [00261] In some embodiments, the one or more additional therapeutic agents is selected from antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulators, and histone deacetylase inhibitors. In some embodiments, the one or more additional therapeutic agent is selected from the following agents, or a pharmaceutically acceptable salt thereof: BCR-ABL inhibitors: e.g. imatinib, inilotinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, danusertib, saracatinib, PF03814735; ALK inhibitors (see Dardaei et al, 2018, Nat Med.; 24(4):512-517): e.g. crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entrecinib, lorlatinib; BRAF inhibitors (see Prahallad et al, 2015, Cell Rep. 12, 1978–1985): e.g. vemurafenib, dabrafenib; FGFR inhibitors: e.g. infigratinib, dovitinib, erdafitinib, BLU-554, AZD4547; FLT3 inhibitors: e.g. sunitinib, midostaurin, tanutinib, sorafenib, lestaurtinib, quizartinib, and crenolanib; MEK Inhibitors (see Fedele et al, 2018, BioRxiv 307876; Torres-Ayuso et al, 2018, Cancer Discov.8, 1210–1212; and Wong et al, 2016, Oncotarget.2016 Oct 4; 7(40): 65676–65695) : e.g. trametinib, cobimetinib, binimetinib, selumetinib; ERK inhibitors: e.g. ulixertinib, MK-8353, LY-3214996; VEGF receptor inhibitors: e.g. bevacizumab, axitinib, aflibercept, brivanib, motesanib, pasireotide, sorafenib; Tyrosine kinase inhibitors: e.g. erlotinib, linifanib, sunitinib, pazopanib; Epidermal growth factor receptor (EGFR) inhibitors: gefitnib, osimertinib, cetuximab, panitumumab; HER2 receptor inhibitors: e.g. trastuzumab, neratinib, lapatinib, lapatinib; MET inhibitors: e.g. crizotinib, cabozantinib; CD20 antibodies: e.g. rituximab, tositumomab, ofatumumab; DNA Synthesis inhibitors: e.g. capecitabine, gemcitabine, nelarabine, hydroxycarbamide; Antineoplastic agents: e.g. oxaliplatin, cisplatin; HER dimerization inhibitors: e.g. pertuzumab; Human Granulocyte colony-stimulating factor (G-CSF) modulators: e.g. filgrastim; Immunomodulators: e.g. afutuzumab, lenalidomide, thalidomide, pomalidomide; CD40 inhibitors: e.g. dacetuzumab; Pro-apoptotic receptor agonists (PARAs): e.g. dulanermin; Heat Shock Protein (HSP) inhibitors: e.g. tanespimycin (17-allylamino-17-desmethoxygeldanamycin); Hedgehog antagonists: e.g. vismodegib; Proteasome inhibitors: e.g. bortezomib; PI3K inhibitors: e.g. pictilisib, dactolisib, buparlisib, taselisib, idelalisib, duvelisib, umbralisib; Phospholipase A2 inhibitors: e.g. anagrelide; BCL-2 inhibitors: e.g. venetoclax; Aromatase inhibitors: exemestane, letrozole, anastrozole, faslodex, tamoxifen; Topoisomerase I inhibitors: e.g. irinotecan, topotecan; Topoisomerase II inhibitors: e.g. etoposide, teniposide; mTOR inhibitors: e.g. temsirolimus, ridaforolimus, everolimus, sirolimus; Osteoclastic bone resorption inhibitors: e.g. zoledronic acid; CD33 Antibody Drug Conjugates: e.g. gemtuzumab ozogamicin; CD22 Antibody Drug Conjugates: e.g. inotuzumab ozogamicin; CD20 Antibody Drug Conjugates: e.g. ibritumomab tiuxetan; Somatostain analogs: e.g. octreotide; Interleukin-11 (IL-11): e.g. oprelvekin; Synthetic erythropoietin: e.g. darbepoetin alfa; Receptor Activator for Nuclear Factor κ B (RANK) inhibitors: e.g. denosumab; Thrombopoietin mimetic peptides: e.g. romiplostim; Cell growth stimulators: e.g. palifermin; Anti-Insulin-like Growth Factor-1 receptor (IGF-1R) antibodies: e.g. figitumumab; Anti-CSl antibodies: e.g. elotuzumab; CD52 antibodies: e.g. alemtuzumab; CTLA- 4 inhibitors: e.g. tremelimumab, ipilimumab; PD1 inhibitors: e.g. nivolumab, pembrolizumab; an immunoadhesin; e.g. pidilizumab, AMP-224; PDL1 inhibitors: e.g. MSB0010718C; YW243.55.S70, MPDL3280A; MEDI-4736, MSB-0010718C, or MDX-1105; LAG-3 inhibitors: e.g. BMS-986016; GITR agonists; GITR fusion proteins and anti-GITR antibodies; Histone deacetylase inhibitors (HDI): e.g. voninostat; Anti-CTLA4 antibodies: e.g. tremelimumab, ipilimumab; Alkylating agents: e.g. temozolomide, dactinomycin, melphalan, altretamine carmustine, bendamustine, busulfan, carboplatin, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine , altretamine, ifosfamide, procarbazine , mechlorethamine, mustine and mechloroethamine, streptozocin, thiotepa; Biologic response modifiers: e.g. bacillus calmette-guerin, denileukin diftitox; Anti-tumor antibiotics: e.g. doxorubicin, bleomycin, daunorubicin , daunorubicin liposomal, mitoxantrone, epirubicin, idarubicin, mitomycin C; Anti- microtubule agents: e.g. estramustine; Cathepsin K inhibitors: e.g. odanacatib; Epothilone analogs: e.g. ixabepilone; TpoR agonists: e.g. eltrombopag; Anti-mitotic agents: e.g. docetaxel; Adrenal steroid inhibitors: e.g. aminoglutethimide; Anti-androgens: e.g. nilutamide; Androgen Receptor inhibitors: e.g. enzalutamide, abiraterone acetate, orteronel, galeterone, and seviteronel, bicalutamide, flutamide; Androgens: e.g. fluoxymesterone; CDK1 inhibitors: e.g. alvocidib, palbociclib, ribociclib, trilaciclib, abemaciclib; Gonadotropin-releasing hormone (GnRH) receptor agonists: e.g. leuprolide or leuprolide acetate; Taxane anti-neoplastic agents: e.g. cabazitaxel, larotaxel; 5-HTla receptor agonists: e.g. xaliproden; HPV vaccines: e.g. Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents: e.g. deferasirox; Anti- metabolites: e.g. claribine, 5-fluorouracil, 6-thioguanine, pemetrexed, cytarabine, cytarabine liposomal, decitabine, hydroxyurea, fludarabine, floxuridine, cladribine, methotrexate, pentostatin; Bisphosphonates: e.g. pamidronate; Demethylating agents: e.g. 5-azacitidine, decitabine; Anti-tumor Plant Alkaloids: e.g. paclitaxel protein-bound; vinblastine, vincristine, vinorelbine, paclitaxel; Retinoids: e.g. alitretinoin, tretinoin, isotretinoin, bexarotene; Glucocorticosteroids: e.g. hydrocortisone, dexamethasone, prednisolone, prednisone, methylprednisolone; Cytokines: e.g. interleukin-2, interleukin-11 (oprevelkin), alpha interferon alfa (IFN-alpha); estrogen receptor downregulators: fulvestrant; Anti-estrogens: e.g. tamoxifen, toremifene; Selective estrogen receptor modulators (SERMs): e.g. raloxifene; Luteinizing hormone releasing hormone (LHRH) agonists: e.g. goserelin; Progesterones: e.g. megestrol; cytotoxic agents: arsenic trioxide, asparaginase (also known as L-asparaginase, Erwinia L- asparaginase; Anti-nausea drugs: e.g. NK-1 receptor antagonists (e.g. casopitant); Cytoprotective agents: e.g. amifostine, leucovorin; and Immune checkpoint inhibitors. The term "immune checkpoints" refers to a group of molecules on the cell surface of CD4 and CD8 T cells. Immune checkpoint molecules include, but are not limited to, Programmed Death 1 (PD-1), Cytotoxic T- Lymphocyte Antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD 137, CD40, and LAG3. Immunotherapeutic agents which can act as immune checkpoint inhibitors useful in the methods of the present disclosure, include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and/or TGFR beta. [00262] In some embodiments, the one or more additional therapeutic agent is selected from the following agents: anti-CDK2 antibodies; cytotoxic agents; Estrogen Receptor-targeted or other endocrine therapies, immune-checkpoint inhibitors, other CDK inhibitors, Receptor Tyrosine Kinase inhibitors, BRAF inhibitors, MEK inhibitors, PI3K inhibitors, SHP2 inhibitors, and SRC inhibitors. (See M. Katoh, Nat. Rev. Clin. Oncol.2019, 16:105-122; Y.K. Chae, et al. Oncotarget 2017, 8:16052-16074; L. Formisano et al., Nat. Comm.2019, 10:1373-1386; and references cited therein.) [00263] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). [00264] A compound described herein may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. [00265] A compound described herein can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound described herein and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound described herein can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. [00266] Those additional agents may be administered separately from a provided compound- containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound described herein in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. [00267] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound described herein may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. [00268] The amount of both a compound described herein and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions described herein should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound described herein can be administered. [00269] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound described herein may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 μg/kg body weight/day of the additional therapeutic agent can be administered. [00270] The amount of additional therapeutic agent present in the compositions described herein will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. [00271] The compounds described herein, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. The present disclosure also contemplates implantable devices coated with a compound described herein. [00272] Any of the compounds and/or compositions of the disclosure may be provided in a kit comprising the compounds and/or compositions. Thus, in some embodiments, the compound and/or composition of the disclosure is provided in a kit. [00273] The disclosure is further described by the following non-limiting Examples. EXAMPLES [00274] Examples are provided herein to facilitate a more complete understanding of the disclosure. The following examples serve to illustrate the exemplary modes of making and practicing the subject matter of the disclosure. However, the scope of the disclosure is not to be construed as limited to specific embodiments disclosed in these examples, which are illustrative only. [00275] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds described herein, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to other classes and subclasses and species of each of these compounds, as described herein. Additional compounds described herein were prepared by methods substantially similar to those described herein in the Examples and methods known to one skilled in the art. [00276] In the description of the synthetic methods described below, unless otherwise stated, it is to be understood that all reaction conditions (for example, reaction solvent, atmosphere, temperature, duration, and workup procedures) are selected from the standard conditions for that reaction, unless otherwise indicated. In the general schemes, it is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. [00277] At least some of the compounds identified as “Intermediates” herein are contemplated as compounds of the disclosure. Example 1 (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate
Figure imgf000601_0001
benzyl (1-(tert-butyl)-3-((2R,4R)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)-1H- pyrazol-5-yl)carbamate
Figure imgf000601_0002
[00278] Step 1: A round bottomed flask was charged with 1-(tert-butyl)-3-((2R,4R)-4-((tert- butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)-1H-pyrazol-5-amine (9.56 g, 28.2 mmol), NaHCO3 (11.8 g 141 mmol), MeCN (100 mL) and a stirbar. Then benzyl carbonochloridate (14.4 g, 84.5 mmol) was added at 0ºC. The solution was stirred at 25 °C for 16 hours. Concentration in vacuum. The mixture was diluted with water (150 mL), and the aqueous phase was extracted with EA (3*150 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered. Concentration in vacuum resulted in benzyl (1-(tert-butyl)-3-((2R,4R)-4-((tert- butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (22 g, 23 mmol, 82 %, 50% Purity) (crude) as a yellow oil. m/z (ES+) [M+H]+ =474.40; HPLC tR = 1.237 min. benzyl (1-(tert-butyl)-3-((2R,4R)-4-hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5- yl)carbamate
Figure imgf000602_0001
[00279] Step 2: A round bottomed flask was charged with benzyl (1-(tert-butyl)-3-((2R,4R)-4- ((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (22 g, 50% Purity, 28 mmol), 4-methylbenzenesulfonic acid (14 g, 84 mmol) in ACN (200 mL) and a stirbar. The solution was stirred for 2 hours at 25 °C. LCMS OK. The resulting mixture was concentrated under vacuum. The mixture was neutralized to ~ pH 7. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with EA (200 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum. The crude product was recrystallized from EA (100 ml) to afford benzyl (1-(tert-butyl)-3-((2R,4R)-4-hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (8.51 g, 23.7 mmol, 85 %) as a white solid. m/z (ES+) [M+H]+ =360.35; HPLC tR = 0.760 min. benzyl (1-(tert-butyl)-3-((2R,4R)-4-(((4-nitrophenoxy)carbonyl)oxy)tetrahydrofuran-2-yl)- 1H-pyrazol-5-yl)carbamate
Figure imgf000602_0002
[00280] Step 3: To a stirred solution of benzyl (1-(tert-butyl)-3-((2R,4R)-4- hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (4.45 g, 12.4 mmol) in DCM (40 mL) was added pyridine (2.94 g, 37.1 mmol) and N,N-dimethylpyridin-4-amine (303 mg, 2.48 mmol) under 0ºC. To above reaction was added 4-nitrophenyl carbonochloridate (3.74 g, 18.6 mmol) under N2. The reaction was stirred at 25 °C for 4 hours. The resulting mixture was concentrated under vacuum to afford a crude benzyl (1-(tert-butyl)-3-((2R,4R)-4-(((4- nitrophenoxy)carbonyl)oxy)tetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (6.2 g, 5.9 mmol, 48 %, 50% Purity) as a light yellow oil. m/z (ES+) [M+H]+ =525.30; HPLC tR = 1.020 min. (3R,5R)-5-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000603_0001
[00281] Step 4: A round bottomed flask was charged with benzyl (1-(tert-butyl)-3-((2R,4R)-4- (((4-nitrophenoxy)carbonyl)oxy)tetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (6.2 g, 12 mmol), 1-methylcyclopropan-1-amine hydrochloride (2.5 g, 24 mmol), THF (60 mL), DIEA (6.1 g, 8.2 mL, 47 mmol) and a stirbar. The solution was stirred for 3 hours at 25 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. concentrated in vacuo resulted in (3R,5R)-5-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (4.6 g, 10 mmol, 85 %) as a white oil. m/z (ES+) [M+H]+ =457.35; HPLC tR = 0.694 min. (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate
Figure imgf000603_0002
[00282] Step 5: A solution of (3R,5R)-5-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H- pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (9.2 g, 20 mmol) in EA/THF=2:1 (90 mL) was bubbling nitrogen through the reaction mixture for 3 times. Then Pd/C (920 mg) was added. After bubbling H2 through the reaction mixture for 3 times. The mixture was stirred at room temperature for 3 hours with H2. The mixture was evaporated and (3R,5R)- 5-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (6.4 g, 19 mmol, 94 %, 95% Purity) was obtained as an white solid without purification for next step directly. m/z (ES+) [M+H]+ =323.35; HPLC tR = 0.528 min. Example 2 (3R,5R)-5-(3-(1-methyl-3-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000604_0001
lithium 3-bromo-1-methyl-1H-pyrazole-5-carboxylate
Figure imgf000604_0002
[00283] Step 1. To a stirred solution of methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (500 mg, 1 Eq, 2.28 mmol) in THF (5 mL) was added LiOH (104 mg, 4.34 mL, 1 molar, 1.9 Eq, 4.34 mmol)in Water at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 0.5 hour at 50C. The mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 10% gradient in 15 min; detector, UV 254 nm, Concentration in vacuo resulted in lithium 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (400 mg, 1.9 mmol, 60 %) as white solid. m/z (ES+) [M+H]+ =207.07; HPLC tR = 0.992 min. (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000605_0001
[00284] .Step 2. To a solution of lithium 1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxylate (25 mg, 0.12 mmol) and (3R,5R)-5-(3-amino-1-(tert-butyl)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (49 mg, 0.15 mmol) in ethyl acetate (1 mL) was added DIEA (160 mg, 1.2 mmol). To above reaction was added T3P (620 mg, 50% Wt in EA, 0.98 mmol) at 0 ºC. The reaction was stirred at 75 °C for overnight. The mixture was quenched with water, filtered and extracted with EA(3*20ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 60% gradient in 30 min; detector, UV 254 nm to afford (3R,5R)-5-(1-(tert-butyl)-5-(1- methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (60 mg, 120 μmol, 97 %) as a white solid. m/z (ES+) [M+H]+ =509.37; HPLC tR = 1.41 min. (3R,5R)-5-(1-(tert-butyl)-3-(1-methyl-3-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000605_0002
[00285] .Step 3. To an 8-mL vial there was added NiCl2 diglyme (1.1 mg, 4.9 µmol), 4,4-di-tert- butyl-2,2-bipyridyl (1.3 mg, 4.9 µmol), (4,4'-Di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-(5- trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (1.1 mg, 0.98 µmol) and (3R,5R)-5-(3-(3-bromo-1-methyl-1H-pyrazole-5-carboxamido)-1-(tert-butyl)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (50 mg, 98 µmol). Reaction was capped and purged with nitrogen 3 times before dissolving solids in 1,4-Dioxane (1.00 mL). To the solution, 1-bromo-2-(trifluoromethoxy)ethane (38 mg, 26 µL, 0.20 mmol), Tris(trimethylsilyl)silane (24 mg, 30 µL, 1 Eq, 98 µmol), and 2,6-lutidine (32 mg, 34 µL, 3 Eq, 0.29 mmol) were added all while sparging with nitrogen. Reaction was then inserted in the Merck Photoreactor, reacting at 100% light intensity for 150 minutes. Reaction was filtered through a pad of celite then concentrated and redissolved in DMSO and placed on an AccQ prep system. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 60% gradient in 30 min; detector, UV 254 nm to afford. (3R,5R)-5-(1-(tert-butyl)-3-(1-methyl-3-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (4 mg, 7 µmol, 8 %) m/z (ES+) [M+H]+ =543.48; HPLC tR = 1.47 min. (3R,5R)-5-(3-(1-methyl-3-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000606_0001
[00286] Step 4. To the residue of (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3- ((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (5 mg, 7 umol) was added FA (2 mL) . The reaction was stirred at 75 °C for 1 h. The mixture was concentrated and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 60% gradient in 30 min; detector, UV 254 nm. Lyophilization yielded (3R,5R)-5-(3-(1-methyl-3-(2- (trifluoromethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (1.3 mg, 2.7 μmol, 26 %, 99.4% Purity) as a white solid. m/z (ES+) [M+H]+ =487.31; HPLC tR = 1.288 min. [00287] Additional compounds prepared according to the methods of Example 2 are depicted in Table 2 below. Table 2. Additional Exemplary Compounds
Figure imgf000607_0001
Example 3 (3R,5R)-5-(3-((2-((S*)-1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5R)-5-(3-((2-((R*)-1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000608_0001
4-chloro-2-(1-methoxyvinyl)pyrazolo[1,5-a]pyrazine
Figure imgf000608_0002
[00288] Step 1. A stirred solution of methyl 4-chloropyrazolo[1,5-a]pyrazine-2-carboxylate (1 g, 1 Eq, 5 mmol) in THF (14 mL) was cooled to 0 °C and treated with Tebbe's Reagent (1eq, 9.4 mL, 0.5 M in toluene) under N2. The reaction was stirred at 0 °C for 30 min. After 30 minutes the solution was warmed to room temperature and stirred for 1 h. The mixture was carefully quenched with (0.1 N) NaOH solution at 0 °C. This mixture was treated with hexanes and the solids removed by filtration through a pad of Celite. The solids were washed with hexanes and the filtrate passed through a second pad of Celite to remove any newly formed solids. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 53% gradient in 8 min; detector, UV 254 nm to afford 4-chloro-2-(1- methoxyvinyl)pyrazolo[1,5-a]pyrazine (460 mg, 2.19 mmol, 50 %) as a white solid. .m/z (ES+) [M+H]+ =210.20; HPLC tR = 0.887 min. (3R,5R)-5-(1-(tert-butyl)-5-((2-(1-methoxyvinyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H- pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000609_0001
[00289] Step 2. To a stirred solution of 4-chloro-2-(1-methoxyvinyl)pyrazolo[1,5-a]pyrazine (100 mg, 1 Eq, 477 μmol) and (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (154 mg, 1 Eq, 477 μmol) in DMF (3 mL) was added Cs2CO3 (466 mg, 3 Eq, 1.43 mmol) and PdCl2(dppf)-CH2Cl2 adduct (77.9 mg, 0.2 Eq, 95.4 μmol) under N2. The reaction was stirred at 80 °C for overnight. The mixture was diluted with water, and the aqueous phase was extracted with EA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 40% to 50% gradient in 10 min; detector, UV 254 nm to afford (3R,5R)-5-(1-(tert-butyl)- 5-((2-(1-methoxyvinyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3- yl (1-methylcyclopropyl)carbamate (80 mg, 0.16 mmol, 34 %) as colorless oil. m/z (ES+) [M+H]+ =496.20; HPLC tR = 0.824 min. (3R,5R)-5-(1-(tert-butyl)-5-((2-(1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H- pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000609_0002
[00290] Step 3. To a stirred solution of (3R,5R)-5-(1-(tert-butyl)-5-((2-(1- methoxyvinyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (230 mg, 1 Eq, 464 μmol) in THF (5 mL) and Ethyl acetate (5 mL) was added Pd/C(49.4 mg, 1 Eq, 464 μmol) under N2. The reaction was stirred at room temperature for 1 h under H2. The mixture was filtered and concentrated to afford (3R,5R)-5-(1-(tert-butyl)-5- ((2-(1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (160 mg, 322 μmol, 69.3 %) as colorless oil. m/z (ES+) [M+H]+ =498.25; HPLC tR = 0.746 min. (3R,5R)-5-(5-((2-(1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1Hpyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000610_0001
[00291] Step 4. To the (3R,5R)-5-(1-(tert-butyl)-5-((2-(1-methoxyethyl)pyrazolo[1,5-a]pyrazin- 4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (160 mg, 1 Eq, 322 μmol) was added FA (5 mL). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 51% gradient in 8 min; detector, UV 254 nm to afford (3R,5R)-5-(5-((2-(1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1Hpyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (90 mg, 0.20 mmol, 63 %) as colorless oil. m/z (ES+) [M+H]+ =442.35; HPLC tR = 0.603 min. (3R,5R)-5-(3-((2-((S*)-1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5R)-5-(3-((2-((R*)-1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000610_0002
[00292] Step 5. The (3R,5R)-5-(5-((2-(1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H- pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (90 mg, 1 Eq, 0.20 mmol) was subjected to Prep-Chiral-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 13 min; Wave Length: 220/254 nm; RT1(min): 6.04; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.8 mL; Number Of Runs: 3). Lyophilization yielded (3R,5R)-5-(3-((2-((S*)-1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4- yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (28.9 mg, 64.7 μmol, 64 %, 98.9% Purity) as a white solid. m/z (ES+) [M+H]+ =442.15; HPLC tR = 1.377 min. 1H NMR (400 MHz, DMSO-d6) 12.36 (s, 1H), 10.00 (s, 1H), 8.05 (s, 1H), 7.53 (s, 1H), 7.41-7.23 (m, 2H), 6.79 (s, 1H), 5.17 (s, 1H), 4.84 (s, 1H), 4.55 (q, J = 6.5 Hz, 1H), 3.85 (s, 2H), 3.22 (s, 3H), 2.68 (s, 1H), 1.93 (d, J = 15.3 Hz, 1H), 1.47 (d, J = 6.5 Hz, 3H), 1.25 (s, 3H), 0.61 (s, 2H), 0.48 (q, J = 4.6 Hz, 2H). [00293] The (3R,5R)-5-(5-((2-(1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol- 3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (90 mg, 1 Eq, 0.20 mmol) was subjected to Prep-Chiral-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 13 min; Wave Length: 220/254 nm; RT2(min): 9.67; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.8 mL; Number Of Runs: 3). Lyophilization yielded (3R,5R)-5-(3-((2-((R*)-1-methoxyethyl)pyrazolo[1,5-a]pyrazin-4- yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (31.1 mg, 63.1 μmol, 62 %, 89.6% Purity) as a white amorphous solid..m/z (ES+) [M+H]+ =442.15; HPLC tR = 1.377 min.1H NMR (400 MHz, DMSO-d6) 12.36 (s, 1H), 10.18 (d, J = 131.9 Hz, 1H), 8.05 (s, 1H), 7.53 (s, 1H), 7.42-7.17 (m, 2H), 6.79 (s, 1H), 5.17 (s, 1H), 4.84 (s, 1H), 4.55 (q, J = 6.5 Hz, 1H), 3.85 (s, 2H), 3.22 (s, 3H), 2.71 (s, 1H), 1.96 (s, 1H), 1.47 (d, J = 6.5 Hz, 3H), 1.25 (s, 3H), 0.60 (d, J = 5.1 Hz, 2H), 0.48 (q, J = 4.5 Hz, 2H). Example 4 (3R,5R)-5-(3-((2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5S)-5-(3-((2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000612_0002
7-chloro-5-(methylthio)-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine
Figure imgf000612_0001
[00294] Step 1. A round bottomed flask was charged with 6-chloro-2-(methylthio)pyrimidin-4- amine (5 g, 1 Eq, 0.03 mol), DMF (20 mL), 3-chloro-1,1,1-trifluoropropan-2-one (6 g, 1.5 Eq, 0.04 mol) was added, and the solution was stirred at 120 °C for 16 hours. The residue was concentrated in vacuo and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, (acetonitrile/water), 0% to 100% gradient in 45 min; detector, UV 254 nm. Concentration in vacuo resulted in 7-chloro-5-(methylthio)-2- (trifluoromethyl)imidazo[1,2-c]pyrimidine (3.4 g, 13 mmol, 40 %) as a yellow amorphous solid. m/z (ES+) [M+H]+ = 267.85; HPLC tR = 0.875 min. 7-chloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-ol
Figure imgf000613_0001
[00295] Step 2. A round bottomed flask was charged with 7-chloro-5-(methylthio)-2- (trifluoromethyl)imidazo[1,2-c]pyrimidine (3.4 g, 1 Eq, 13 mmol), MeOH:H2O=2:1 (20 mL), LiOH (1.2 g, 4 Eq, 51 mmol) was added, and the solution was stirred at 25 ºC for 3 hours. The reaction mixture was adjusted the pH value to 7-8 with 1 N HCl solution. The residue was concentrated in vacuo and diluted with water (15 mL), and the aqueous phase was extracted with EA (50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered. Concentration in vacuo resulted in 7-chloro-2-(trifluoromethyl)imidazo[1,2- c]pyrimidin-5-ol (2.9 g, 12 mmol, 96 %) as a brown amorphous solid. m/z (ES+) [M+H]+ = 237.90; HPLC tR = 0.700 min. 5,7-dichloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine
Figure imgf000613_0002
[00296] Step 3. A round bottomed flask was charged with 7-chloro-2- (trifluoromethyl)imidazo[1,2-c]pyrimidin-5-ol (1 g, 1 Eq, 4 mmol), POCl3 (15 mL), DIEA (3 g, 4 mL, 5 Eq, 0.02 mol) was added, and the solution was stirred at 80 ºC for 3 hours. The solution was concentrated in vacuo and quenched with NaHCO3 solution (0 ºC) and adjust the pH value to 7-8 with NaHCO3. The aqueous phase was extracted with EA (40 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered. Concentration in vacuo resulted in 5,7-dichloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine (840 mg, 3.28 mmol, 80 %) as a brown oil. m/z (ES+) [M+H]+ = 255.90; HPLC tR = 0.842 min. 5-bromo-7-chloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine
Figure imgf000613_0003
[00297] Step 4. A round bottomed flask was charged with 5,7-dichloro-2- (trifluoromethyl)imidazo[1,2-c]pyrimidine (700 mg, 1 Eq, 2.73 mmol), ACN (10 mL), TMSBr (837 mg, 2 Eq, 5.47 mmol) was added, and the solution was stirred at 40 °C for 3 hour. The crude product was purified by silica gel chromatography (10 g column; eluting with PE/EA; ratio:15/1). Concentration in vacuo resulted in 5-bromo-7-chloro-2-(trifluoromethyl)imidazo[1,2- c]pyrimidine (720 mg, 2.40 mmol, 87.6 %) as a brown amorphous solid. m/z (ES+) [M+H]+ = 299.80; HPLC tR = 0.867 min. (3R,5R)-5-(1-(tert-butyl)-5-((7-chloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5- yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000614_0001
[00298] Step 5. A resealable reaction vial was charged with 5-bromo-7-chloro-2- (trifluoromethyl)imidazo[1,2-c]pyrimidine (550 mg, 1 Eq, 1.83 mmol), DMF(5 mL), (3R,5R)-5- (5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (885 mg, 1.5 Eq, 2.75 mmol), potassium carbonate (1.01 g, 4 Eq, 7.32 mmol) and PdCl2(dppf) (201 mg, 0.15 Eq, 275 μmol) was added. The resulting mixture was stirred at 80 ºC for 2.5 hours under nitrogen atmosphere. The residue was concentrated in vacuo and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, (acetonitrile/water), 0% to 100% gradient in 45 min; detector, UV 254 nm. Lyophilization yielded resulted in (3R,5R)-5-(1-(tert-butyl)-5-((7-chloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5- yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (295 mg, 0.33 mmol, 18 %, 60% Purity) as a yellow amorphous solid. m/z (ES+) [M+H]+ =542.05; HPLC tR = 0.900 min. (3R,5R)-5-(3-((2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5S)-5-(3-((2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000615_0001
[00299] Step 6. A round bottomed flask was charged with (3R,5R)-5-(1-(tert-butyl)-5-((2- (trifluoromethyl)imidazo[1,2c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (140 mg, 1 Eq, 276 μmol), FA (6 mL) was added, and the solution was stirred at 100 ºC for 16 hours. The residue was concentrated in vacuo and purified by Pre- HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 44% B in 8 min, 44% B; Wave Length: 254; 220 nm; RT1(min): 6.5, 7.48(min)). Lyophilization yielded resulted in (3R,5R)-5-(3-((2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol- 5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (1.9 mg, 4.2 μmol, 1.5 %, m/z (ES+) [M+H]+ = 452.15; HPLC tR = 1.178 min) as an off-white amorphous solid and (3R,5S)-5-(3-((2- (trifluoromethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (2 mg, 4 μmol, 2 %, m/z (ES+) [M+H]+ = 452.15; HPLC tR = 1.258 min) as a white amorphous solid. Example 5 (3R,5R)-5-(3-(1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxamido)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5R)-5-(3-(3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000616_0001
methyl 3-(bromodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate methyl 3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate
Figure imgf000616_0002
[00300] Step 1. To a mixture of methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (400 mg, 2.56 mmol), Dioxane (5 mL) was added NaH (0.18 g, 7.69 mmol) in portions at 25 °C under nitrogen atmosphere. The mixture was stirred for 30 min at 25 °C prior addition of 2-bromo-2,2- difluoroacetic acid sodium salt (608 mg, 3.07 mmol). The mixture was stirred for 30 h at 25 °C. The solid was filtered out. The filtrate was concentrated under vacuum. HCl in Dioxane (5 mL) was added, and concentrated in vacuo. DCM (5mL) and XeF2 (1.31 g, 7.69 mmol) were added, and the mixture was stirred for 30 min at 25 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered. Concentration in vacuo resulted in a mixture of methyl 3-(bromodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate and methyl 3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate (180 mg, 26.8 %) as a yellow oil. [00301] methyl 3-(bromodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate: m/z (ES+) [M+H]+ =224.95; HPLC tR = 0.875 min. [00302] methyl 3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate: m/z (ES+) [M+H]+ =240.90; HPLC tR = 0.875 min. 1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxylic acid 3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid
Figure imgf000617_0001
[00303] Step 2. A resealable reaction vial was charged with a mixture of methyl 1-methyl-3- (trifluoromethoxy)-1H-pyrazole-5-carboxylate and methyl 3-(chlorodifluoromethoxy)-1-methyl- 1H-pyrazole-5-carboxylate (160 mg, 0.70 mmol), NaOH ( 0.86 mL, 0.86 mmol), MeOH (5 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 1 h at 25 °C. The reaction mixture was diluted with H2O (20 mL), and the aqueous phase was extracted with EA (20 mL) three times. then adjusted to pH 1~3 with 1M HCl, and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo resulted in a mixture of 1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxylic acid and 3- (chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid (120 mg, 80 %) as a colourless oil. [00304] 1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxylic acid: m/z (ES+) [M+H]+ =210.95; HPLC tR = 0.750 min. [00305] 3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid: m/z (ES+) [M+H]+ =226.90; HPLC tR = 0.750 min. (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxamido)- 1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5R)-5-(1-(tert-butyl)-5-(3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000618_0001
[00306] Step 3. To a mixture of 1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxylic acid and 3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid (109 mg, 0.50 mmol), DIEA (0.41 g, 0.55 mL, 3.1 mmol) and (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (0.10 g, 0.31 mmol) in EA (5 mL) was added T3P (1.60 g, 50% wt, 2.5 mmol in EA) drop wise at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h at 80 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered. Concentration in vacuo resulted in a mixture of (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxamido)-1H- pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate and (3R,5R)-5-(1-(tert- butyl)-5-(3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (300 mg, crude) as a yellow oil. [00307] (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate: m/z (ES+) [M+H]+ =515.15; HPLC tR = 1.158 min. [00308] (3R,5R)-5-(1-(tert-butyl)-5-(3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate: m/z (ES+) [M+H]+ =531.10; HPLC tR = 1.178 min. (3R,5R)-5-(3-(1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxamido)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5R)-5-(3-(3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000619_0001
[00309] Step 4. A resealable reaction vial was charged with a mixture of (3R,5R)-5-(1-(tert-butyl)- 5-(1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate and (3R,5R)-5-(1-(tert-butyl)-5-(3- (chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (190 mg,crude), FA (5 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 1.5 h at 70 °C. The reaction concentrated in vacuo. The resulting crude material was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 55% B in 7 min, 55% B; Wave Length: 220 nm; RT1(min): 7.27). Lyophilization yielded (3R,5R)-5-(3-(1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxamido)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (38.6 mg, 22.8 %) as a white amorphous solid. m/z (ES+) [M+H]+ =459.15; HPLC tR = 1.318 min.1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 6.54 (s, 1H), 5.16 (s, 1H), 4.84 (t, J = 7.9 Hz, 1H), 4.06 (s, 3H), 3.84 (d, J = 4.6 Hz, 2H), 2.70 (dt, J = 14.4, 7.5 Hz, 1H), 1.93 (t, J = 10.3 Hz, 1H), 1.25 (s, 3H), 0.61 (d, J = 5.1 Hz, 2H), 0.48 (q, J = 4.6 Hz, 2H). [00310] A resealable reaction vial was charged with a mixture of (3R,5R)-5-(1-(tert-butyl)-5-(1- methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate and (3R,5R)-5-(1-(tert-butyl)-5-(3-(chlorodifluoromethoxy)-1- methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (190 mg,crude), FA (5 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 1.5 h at 70 °C. The reaction concentrated in vacuo. The resulting crude material was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 55% B in 7 min, 55% B; Wave Length: 220 nm; RT1(min): 7.27). Lyophilization yielded (3R,5R)-5-(3-(3- (chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (50 mg, crude) as a white amorphous solid. The resulting crude material was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeOH--HPLC; Flow rate: 60 mL/min; Gradient: 49% B to 67% B in 8 min, 67% B; Wave Length: 254 nm; RT1(min): 7.85). Lyophilization yielded (3R,5R)-5-(3-(3-(chlorodifluoromethoxy)-1- methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (9.3 mg, 21 %) as a white amorphous solid. m/z (ES+) [M+H]+ =475.15; HPLC tR = 0.876 min. 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 11.03 (s, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 6.56 (s, 1H), 5.16 (s, 1H), 4.85 (s, 1H), 4.07 (s, 3H), 3.85 (s, 2H), 2.70 (dt, J = 14.0, 7.2 Hz, 1H), 1.93 (s, 1H), 1.25 (s, 3H), 0.62 (s, 2H), 0.48 (s, 2H). [00311] Additional compounds prepared according to the methods of Example 5 are depicted in Table 3 below. Table 3. Additional Exemplary Compounds
Figure imgf000620_0001
Example 6 (3R,5R)-5-(3-(1-methyl-3-((S*)-2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5R)-5-(3-(1-methyl-3-((R*)-2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000621_0001
methyl 1-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazole-5-carboxylate
Figure imgf000621_0002
[00312] Step 1. A resealable reaction vial was charged with methyl 3-formyl-1-methyl-1H- pyrazole-5-carboxylate (500 mg, 2.97 mmol), trimethyl(trifluoromethyl)silane (719 mg, 5.06 mmol), TBAF (155 mg, 0.60 mmol), THF (5 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 3 h at 25 °C. The reaction concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. Concentration in vacuo resulted in methyl 1-methyl-3-(2,2,2- trifluoro-1-hydroxyethyl)-1H-pyrazole-5-carboxylate (400 mg, crude) as a colorless oil. m/z (ES+) [M+H]+ =239.20; HPLC tR = 0.720 min. methyl 1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5-carboxylate
Figure imgf000622_0001
[00313] Step 2. To a mixture of methyl 1-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazole- 5-carboxylate (390 mg, 1.64 mmol) in DMF (5 mL) was added NaH (0.12 g, 4.91 mmol) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 5 min at 0 °C prior addition of iodomethane (697 mg, 4.91 mmol). The mixture was stirred for 1h at 25 °C. The reaction solution is directly used for the next step. m/z (ES+) [M+H]+ =253.00; HPLC tR = 0.788 min. 1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5-carboxylic acid
Figure imgf000622_0002
[00314] Step 3. Above reaction solution was added NaOH (3.27 mL, 3.27 mmol) and stirred for 1 h at 25 °C. The reaction mixture was diluted with H2O (20 mL), and the aqueous phase was extracted with EA (30 mL) three times. then adjusted to pH 1~3 with 1 M HCl. and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo resulted in 1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5-carboxylic acid (180 mg, 46.2 %) as a colorless oil. m/z (ES+) [M+H]+ =239.20; HPLC tR = 0.720 min. (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000623_0001
[00315] Step 4. To a mixture of 1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5- carboxylic acid (160 mg, 0.67 mmol), DIEA (722 mg, 5.58 mmol) and (3R,5R)-5-(5-amino-1- (tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (180 mg, 0.56 mmol) in EA (5 mL) was added T3P (6.39 g, 10.00 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h at 80 °C. The reaction mixture was diluted with H2O (30 mL), and the aqueous phase was extracted with EA (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo resulted in (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3-(2,2,2-trifluoro-1- methoxyethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (400 mg, crude) as a yellow oil. m/z (ES+) [M+H]+ =543.45; HPLC tR = 0.945 min. (3R,5R)-5-(3-(1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5-carboxamido)- 1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000623_0002
[00316] Step 5. A resealable reaction vial was charged with (3R,5R)-5-(1-(tert-butyl)-5-(1- methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (380 mg, 0.70 mmol), FA (5 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 2 h at 75 °C. The reaction concentrated in vacuo. The resulting crude material was purified by Pre-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 26% B to 44% B in 8 min, 44% B; Wave Length: 220 nm; RT1(min): 7.35). Lyophilization yielded (3R,5R)-5-(3-(1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (190 mg, 55.8 %) as a white solid. m/z (ES+) [M+H]+ =487.30; HPLC tR = 0.820 min. (3R,5R)-5-(3-(1-methyl-3-((S*)-2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5R)-5-(3-(1-methyl-3-((R*)-2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000624_0001
[00317] Step 6. (3R,5R)-5-(3-(1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (189 mg, 0.39 mmol) was purified by chiral Pre-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 10 min; Wave Length: 220/254 nm; RT1(min): 5.27; RT2(min): 7.46; Sample Solvent: EtOH: DCM=1: 1-HPLC; Injection Volume: 0.45 mL; Number Of Runs: 5). Lyophilization yielded (3R,5R)-5-(3-(1-methyl-3-((S*)-2,2,2-trifluoro-1- methoxyethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (47.5 mg, 50.3 %) as an amorphous white solid. m/z (ES+) [M+H]+ =487.20; HPLC tR = 0.948 min.1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.94 (s, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 6.56 (s, 1H), 5.16 (s, 1H), 5.03 (q, J = 6.9 Hz, 1H), 4.85 (s, 1H), 4.11 (s, 3H), 3.85 (s, 2H), 3.35 (s, 3H), 2.71 (dd, J = 14.3, 7.5 Hz, 1H), 1.93 (s, 1H), 1.25 (s, 3H), 0.62 (s, 2H), 0.48 (q, J = 5.1, 4.7 Hz, 2H) [00318] (3R,5R)-5-(3-(1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (189 mg, 0.39 mmol) was purified by chiral Pre-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 10 min; Wave Length: 220/254 nm; RT1(min): 5.27; RT2(min): 7.46; Sample Solvent: EtOH: DCM=1: 1-HPLC; Injection Volume: 0.45 mL; Number Of Runs: 5). Lyophilization yielded (3R,5R)-5-(3-(1-methyl-3-((R*)-2,2,2-trifluoro-1- methoxyethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (38.6 mg, 40.8 %) as an amorphous white solid. m/z (ES+) [M+H]+ =487.20; HPLC tR = 0.948 min.1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.94 (s, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 6.56 (s, 1H), 5.16 (s, 1H), 5.03 (q, J = 7.0 Hz, 1H), 4.85 (s, 1H), 4.11 (s, 3H), 3.85 (s, 2H), 3.35 (s, 3H), 2.71 (dd, J = 14.4, 7.4 Hz, 1H), 1.93 (s, 1H), 1.25 (s, 3H), 0.62 (s, 2H), 0.55 (d, J = 13.0 Hz, 1H), 0.48 (q, J = 5.1, 4.7 Hz, 2H). Example 7 (3R,5R)-5-(3-(3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000626_0002
ethyl 3-(chloromethyl)-1H-pyrazole-5-carboxylate
Figure imgf000626_0001
[00319] Step 1. A resealable reaction vial was charged with ethyl 3-(hydroxymethyl)-1H- pyrazole-5-carboxylate (2.00 g, 0.01 mol), SOCl2 (20 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 2 h at 80 °C. The reactiom concentrated in vacuo. The residue was diluted with water, then adjusted to pH 6~7 with sodium bicarbonate. The aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered. Concentration in vacuo resulted in ethyl 3-(chloromethyl)-1H-pyrazole-5-carboxylate (2.20 g, crude) as a colorless oil. m/z (ES+) [M+H]+ =189.20; HPLC tR = 0.645 min. ethyl 3-(methoxymethyl)-1H-pyrazole-5-carboxylate
Figure imgf000627_0001
[00320] Step 2. To a mixture of ethyl 3-(chloromethyl)-1H-pyrazole-5-carboxylate (2.20 g, 12.00 mmol) in MeOH (20 mL) was added NaOMe (0.82 g, 15.00 mmol) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 12 h at 25 °C. The reaction concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. Concentration in vacuo resulted in ethyl 3-(methoxymethyl)-1H-pyrazole-5-carboxylate (1.60 g, 74 %) as a colorless oil. m/z (ES+) [M+H]+ =185.05; HPLC tR = 0.633 min. ethyl 3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxylate
Figure imgf000627_0002
[00321] Step 3. SiO2-OH (34 mg, 0.42 mmol) was added ClSO3H (49 mg, 0.42 mmol) dropwise at 25 °C under nitrogen atmosphere. The mixture was stirred for 2 h at 25 °C. A resealable reaction vial was charged with ethyl 3-(methoxymethyl)-1H-pyrazole-5-carboxylate (600 mg, 3.26 mmol), HDMS (10 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 2 h at 125 °C. The solid was filtered out. The filtrate was concentrated under vacuum. DCM (10 mL) was added, then 3,3-dimethyl-1-(trifluoromethyl)-1,3-dihydro-1l3- benzo[d][1,2]iodaoxole (1.40 g, 4.20 mmol), LiNTf2 (0.15 g, 0.51 mmol) and HNTf2 (0.14 g, 0.51 mmol) were added before being evacuated and purged with nitrogen three times, and the mixture was stirred for 16 h at 40 °C. The reaction concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. Concentration in vacuo resulted in ethyl 3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxylate (140 mg, crude) as a colorless oil. m/z (ES+) [M+H]+ =253.005; HPLC tR = 0.867 min. 3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid
Figure imgf000628_0001
[00322] Step 4. A resealable reaction vial was charged with ethyl 3-(methoxymethyl)-1- (trifluoromethyl)-1H-pyrazole-5-carboxylate (180 mg, 0.21 mmol), NaOH (428 µL, 428 µmol), MeOH (5 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 1 h at 25 °C. The reaction mixture was diluted with H2O (20 mL), and the aqueous phase was extracted with EA (20 mL) three times, then adjusted to pH 1~3 with 1M HCl. The aqueous phase was extracted with EA (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered. Concentration in vacuo resulted in 3- (methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (50 mg, crude) as a colorless oil. m/z (ES+) [M+H]+ =225.05; HPLC tR = 0.567 min. (3R,5R)-5-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000628_0002
[00323] Step 5. To a mixture of 3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5- carboxylic acid (119 mg, 0.53 mmol), DIEA (625 mg, 4.84 mmol) and (3R,5R)-5-(5-amino-1- (tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (156 mg, 0.48 mmol) in EA (5 mL) was added T3P (4.92 g, 50% wt 3.87 mmol in EA) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 12 h at 80 °C. The reaction mixture was diluted with H2O (20 mL), and the aqueous phase was extracted with EA (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered. Concentration in vacuo resulted in (3R,5R)-5-(1-(tert-butyl)-5-(3-(methoxymethyl)-1- (trifluoromethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (200 mg, 78.2 %) as a yellow oil. m/z (ES+) [M+H]+ =529.10; HPLC tR = 0.850 min. (3R,5R)-5-(3-(3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000629_0001
[00324] Step 6. A resealable reaction vial was charged with (3R,5R)-5-(1-(tert-butyl)-5-(3- (methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (250 mg, 0.47 mmol), FA (5 mL), and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 3 h at 70 °C. The reaction concentrated in vacuo. The resulting crude material was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 45% B in 7 min, 45% B; Wave Length: 220 nm; RT1(min): 7.63). Lyophilization yielded (3R,5R)-5-(3- (3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (86.8 mg, 38.8 %) as an off white solid. m/z (ES+) [M+H]+ =473.15; HPLC tR = 0.903 min. 1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 11.36 (s, 1H), 7.52 (s, 1H), 7.17 (s, 1H), 6.55 (s, 1H), 5.16 (s, 1H), 4.85 (s, 1H), 4.47 (s, 2H), 3.85 (s, 2H), 3.33 (s, 3H), 2.74 - 2.66 (m, 1H), 1.92 (s, 1H), 1.24 (s, 3H), 0.67 - 0.43 (m, 4H). Example 8 (3R,5R)-5-(3-(1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000630_0001
methyl 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylate
Figure imgf000630_0002
[00325] Step 1. To a mixture of methyl 1H-pyrazole-4-carboxylate (110 mg, 0.87 mmol) in DMF (5 mL) was added 1-bromo-2-(trifluoromethoxy)ethane (252 mg, 1.31 mmol) and K2CO3 (362 mg, 2.62 mmol). The mixture was stirred for 1 hour at 50 °C. The reaction mixture was diluted with H2O (15 mL), and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered. Concentration in vacuo resulted in methyl 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylate (170 mg, 81.8 %) as a white solid. m/z (ES+) [M+H]+ =238.95; HPLC tR = 0.742 min. 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid
Figure imgf000630_0003
[00326] Step 2. A resealable reaction vial was charged with methyl 1-(2-(trifluoromethoxy)ethyl)- 1H-pyrazole-4-carboxylate (160 mg, 0.67 mmol) and NaOH (54 mg, 1.34 mmol), MeOH (4 mL), and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 1 hour at 25 °C. The reaction mixture was diluted with H2O (15 mL), and the aqueous phase was extracted with EA (30 mL) three times. The pH value of the aqueous layer was adjusted to 1~3 with 1 M HCl. The aqueous layer was extracted with 3x30 mL of ethyl acetate. The organic layers were combined, washed with brine, dried. Concentration in vacuo resulted in 1-(2- (trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (100 mg, 66.4 %) as a white solid. m/z (ES+) [M+H]+ =224.95; HPLC tR = 0.458 min. (3R,5R)-5-(1-(tert-butyl)-5-(1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxamido)- 1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000631_0001
[00327] Step 3. To a mixture of 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (91 mg, 0.41 mmol) in EA (5 mL) was added (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (110 mg, 0.34 mmol) and DIEA (441 mg, 3.41 mmol), then T3P (2.6 g, 50 wt, 2.04 mmol in EA) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 2.5 h at 80 °C. The reaction mixture was diluted with H2O (15 mL), and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered. Concentration in vacuo resulted in (3R,5R)-5-(1-(tert-butyl)-5-(1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H- pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (150 mg, 83.2 %) as a white solid. m/z (ES+) [M+H]+ =529.15; HPLC tR = 0.783 min. (3R,5R)-5-(3-(1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000632_0001
[00328] Step 4. A resealable reaction vial was charged with (3R,5R)-5-(1-(tert-butyl)-5-(1-(2- (trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (145 mg, 0.27 mmol), FA (6 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 1.5 hour at 75 °C. The reaction concentrated in vacuo. The resulting crude material was purified by Pre-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 40% B in 8 min, 40% B; Wave Length: 254 nm; RT1(min): 7.57;). Lyophilization yielded (3R,5R)-5-(3-(1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (72.1 mg, 55.6 %) as a white amorphous solid. m/z (ES+) [M+H]+ =473.35; HPLC tR = 0.687 min.1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 10.49 (s, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 7.53 (s, 1H), 6.54 (s, 1H), 5.16 (s, 1H), 4.81 (s, 1H), 4.51 - 4.44 (m, 4H), 3.84 (s, 2H), 2.75 (s, 1H), 1.91 (s, 1H), 1.25 (s, 3H), 0.61 (s, 2H), 0.48 (s, 2H). [00329] Additional compounds prepared according to the methods of Example 8 are depicted in Table 4 below.
Table 4. Additional Exemplary Compounds
Figure imgf000633_0003
Example 9 (3R,5R)-5-(3-((2-((trifluoromethoxy)methyl) pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H- pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000633_0002
4-bromo-2-(bromomethyl)pyrazolo[1,5-a]pyrazine
Figure imgf000633_0001
[00330] Step 1. To a stirred solution of (4-chloropyrazolo[1,5-a]pyrazin-2-yl)methanol (2 g, 1 Eq, 0.01 mol) in MeCN (20 mL) was added PBr3 (4 g, 2 mL, 1.5Eq, 0.02 mol) at 0ºC under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 70 °C. The mixture was adjusted to PH=7 and extracted with EtOAc (3 x 40mL). The combined organic layers were washed with brine (1x40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-bromo-2-(bromomethyl)pyrazolo[1,5-a]pyrazine (1.5 g, 5.2 mmol, 50 %) as yellow solid. m/z (ES+) [M+H]+ =290.80; HPLC tR = 0.850 min. 4-bromo-2-((trifluoromethoxy)methyl)pyrazolo[1,5-a]pyrazine
Figure imgf000634_0001
[00331] Step 2. To a stirred solution of Silver fluoride (2.0 g, 0.34 mL, 3 Eq, 15 mmol) in MeCN (30 mL) was added Trifluoromethyltriflate (4.5 g, 4 Eq, 21mmol) at -30 C under nitrogen atmosphere. The mixture was stirred for 1h at -30 C. Then 4-bromo-2-(bromomethyl)pyrazolo[1,5- a]pyrazine (1.5 g, 1 Eq, 5.2 mmol) was added. The resulting mixture was stirred for 16 hour at 25 °C. The resulting mixture was filtered. The residue was purified by silica gel chromatography with the following conditions: EtOAc in PE, 0% to 25% gradient in 20 min to afford 4-bromo-2- ((trifluoromethoxy)methyl)pyrazolo[1,5-a]pyrazine (600 mg,2.03 mmol, 39 %) as yellow oil. m/z (ES+) [M+H]+ =295.80; HPLC tR = 0.848 min. (3R,5R)-5-(1-(tert-butyl)-5-((2-((trifluoromethoxy)methyl)pyrazolo[1,5-a]pyrazin-4- yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000634_0002
[00332] Step 3. To a stirred solution of (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (327 mg, 1Eq, 1.01 mmol) in 1,4- Dioxane (3 mL) was added 4-bromo-2-((trifluoromethoxy)methyl)pyrazolo[1,5-a]pyrazine (300 mg, 1 Eq, 1.01mmol), K2CO3 (420 mg, 3 Eq, 3.04 mmol), xantphos (235 mg, 0.4 Eq, 405 μmol), Pd2(dba)3 (186 mg, 0.2 Eq, 203 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 60 °C. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 90% gradient in 15 min; detector, UV 254 nm. Concentration in vacuo resulted in (3R,5R)-5-(1-(tert-butyl)-5-((2-((trifluoromethoxy)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)- 1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (160 mg, 298 μmol, 29.4 %) as yellow oil. m/z (ES+) [M+H]+ =538.15; HPLC tR = 0.888 min. (3R,5R)-5-(3-((2-((trifluoromethoxy)methyl) pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H- pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000635_0001
[00333] Step 4. (3R,5R)-5-(1-(tert-butyl)-5-((2-((trifluoromethoxy)methyl)pyrazolo[1,5- a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (150 mg, 1 Eq, 279 μmol) was added FA (3 mL). The reaction was stirred at 70 °C for 1 hour. The mixture was concentrated and purified by Prep-HPLC( Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 40% B in 8 min, 40% B; Wave Length: 254 nm; RT1(min): 6.65). Lyophilization yielded (3R,5R)-5-(3-((2-((trifluoromethoxy)methyl) pyrazolo[1,5- a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (12.5 mg, 26.0 μmol, 9.30 %) as a white solid. m/z (ES+) [M+H]+ =482.20; HPLC tR = 0.696 min. 1H NMR (400 MHz, DMSO-d6) 12.39 (s, 1H), 10.16 (s, 1H), 8.10 (s, 1H), 7.58-7.21 (m, 3H), 6.80 (s, 1H), 5.35 (s, 2H), 5.17 (s, 1H), 4.92 (d, J = 49.7 Hz, 1H), 3.86 (s, 2H), 2.73 (dd, J = 14.7, 7.2 Hz, 1H), 1.96 (d, J = 11.2 Hz, 1H), 1.25 (s, 3H), 0.60 (d, J = 5.3 Hz, 2H), 0.48 (q, J = 4.5 Hz, 2H). [00334] Additional compounds prepared according to the methods of Example 9 are depicted in Table 5 below. Table 5. Additional Exemplary Compounds
Figure imgf000636_0001
Example 10 (3R,5R)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5S)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000637_0001
ethyl 7-chloro-5-hydroxyimidazo[1,2-c]pyrimidine-2-carboxylate
Figure imgf000637_0002
[00335] Step 1. A round bottomed flask was charged with 2,6-dichloropyrimidin-4-amine (3 g, 0.02 mol), ethyl 3-bromo-2-oxopropanoate (9 g, 0.05 mol) and a stirbar. AcOH (32 mL) was added, and the solution was stirred for 3 hours at 120 °C. The mixture was concentrated in vacuum. The mixture was adjusted pH value to 6-7. The aqueous phase was extracted with DCM (50mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (10 g column; eluting with DCM/MEOH; ratio:30/1). Concentration in vacuum. The precipitated solids were collected by filtration and washed with EA (20 mL) to afford ethyl 7-chloro-5- hydroxyimidazo[1,2-c]pyrimidine-2-carboxylate (1.09 g, 4.51 mmol, 20 %) as a light pink solid. m/z (ES+) [M+H] + = 242.05; HPLC tR = 0.467 min. ethyl 5-hydroxyimidazo[1,2-c]pyrimidine-2-carboxylate
Figure imgf000638_0001
[00336] Step 2. A stirred mixture of ethyl 7-chloro-5-hydroxyimidazo[1,2-c]pyrimidine-2- carboxylate (1.09 g, 4.51 mmol) and Pd/C (120 mg, 1.13 mmol) in MeOH (15 mL) was treated with H2 for 1 hour at 25 °C. The reaction mixture was filtered through a pad of Celite, the pad was washed with MeOH (50 ml), and the filtrate was concentrated in vacuum to afford ethyl 5- hydroxyimidazo[1,2-c]pyrimidine-2-carboxylate (910 mg, 4.39 mmol, 97.4 %) as a yellow solid. m/z (ES+) [M+H] + = 208.05; HPLC tR = 0.615 min. 2-(hydroxymethyl)imidazo[1,2-c]pyrimidin-5-ol
Figure imgf000638_0002
[00337] Step 3. To a mixture of ethyl 5-hydroxyimidazo[1,2-c]pyrimidine-2-carboxylate (500 mg, 2.41 mmol) in THF (15 mL) was added LAH (3.62 mL of a solution 1M in THF, 3.62 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 12 hours at 25 °C. The mixture was quenched with Na2SO4·10H2O. The reaction mixture was filtered, the pad was washed with tepidity DCM/MeOH=4/1(100 ml) and MeOH/H2O=4/1(100 ml), and the filtrate was concentrated in vacuum to afford 2-(hydroxymethyl)imidazo[1,2-c]pyrimidin-5-ol (480 mg, 2.91 mmol, crude) as a brown solid. m/z (ES+) [M+H] + = 166.05; HPLC tR = 0.233 min. 2-(chloromethyl)imidazo[1,2-c]pyrimidin-5-ol
Figure imgf000639_0001
[00338] Step 4. A round bottomed flask was charged with 2-(hydroxymethyl)imidazo[1,2- c]pyrimidin-5-ol (2.7 g,16 mmol), SOCl2 (19 g, 12 mL,0.16 mol), DMF (0.01 mL), toluene (30 mL) and a stirbar. The solution was stirred for 5 hours at 110 °C. The mixture was concentrated in vacuum to afford 2-(chloromethyl)imidazo[1,2-c]pyrimidin-5-ol (2.1 g, 11 mmol, crude) as a brown solid. m/z (ES+) [M+H] + = 184.00; HPLC tR = 0.565 min. 2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-ol
Figure imgf000639_0002
[00339] Step 5. A round bottomed flask was charged with 2-(chloromethyl)imidazo[1,2- c]pyrimidin-5-ol (2.1 g, 11 mmol), Sodium methoxide (10 g, 11 mL, 30% Wt, 57 mmol) and a stirbar. MeOH (40 mL) was added, and the solution was stirred for 16 hours at 25 °C. The mixture was concentrated in vacuum. Adjusted pH value of the mixture to 6-7 with 2M HCl. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 20% gradient in 25 min; detector, UV 254 nm to afford 2- (methoxymethyl)imidazo[1,2-c]pyrimidin-5-ol (380 mg, 2.12 mmol, 19 %) as a white amorphous solid. m/z (ES+) [M+H] + = 180.05; HPLC tR = 0.432 min 5-chloro-2-(methoxymethyl)imidazo[1,2-c]pyrimidine
Figure imgf000639_0003
[00340] Step 6. A round bottomed flask was charged with 2-(methoxymethyl)imidazo[1,2- c]pyrimidin-5-ol (380 mg, 2.12 mmol), DIEA (5.48 g, 7.39 mL, 42.4 mmol), POCl3 (25 mL) and a stirbar. The solution was stirred for 6 hours at 100 °C. The mixture was concentrated in vacuum. Adjusted pH value of the mixture to 6-7 with NaHCO3.The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with EA (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 18 min; detector, UV 254 nm to afford 5-chloro-2-(methoxymethyl)imidazo[1,2-c]pyrimidine (320 mg, 1.62 mmol, 76.4 %) as a white solid. m/z (ES+) [M+H] + = 198.00; HPLC tR =0.656min (3R,5R)-5-(1-(tert-butyl)-5-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H- pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000640_0001
[00341] Step 7. A resealable reaction vial was charged with (3R,5R)-5-(5-amino-1-(tert-butyl)- 1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (475 mg, 1.47 mmol), 5- chloro-2-(methoxymethyl)imidazo[1,2-c]pyrimidine (320 mg, 1.62 mmol), xantphos (426 mg, 736 µmol), Pd2(dba)3 (270 mg, 294 µmol), K2CO3 (610 mg, 4.42 mmol) and a stirbar before being evacuated and purged with nitrogen three times.1,4-Dioxane (8 mL) was added, and the mixture was stirred for 12 hours at 80 °C. The mixture was quenched with water (20 mL), and the aqueous phase was extracted with EA (30mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 80% gradient in 18 min; detector, UV 254 nm to afford (3R,5R)-5- (1-(tert-butyl)-5-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-3- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (260 mg, 538 µmol, 36.5 %) as a white solid. m/z (ES+) [M+H] + = 484.30; HPLC tR =0.913 min. (3R,5R)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate (3R,5S)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate
Figure imgf000641_0001
[00342] Step 8. A round bottomed flask was charged with (3R,5R)-5-(1-(tert-butyl)-5-((2- (methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (300 mg, 620 µmol) and a stirbar. HCOOH (8 mL) was added, and the solution was stirred for 5 hours at 100 °C. The mixture was adjusted pH value to 6-7. The aqueous phase was extracted with EA (20mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum. The resulting crude material was purified by Pre-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to 32% B in 11 min, 32% B to 40% B in 12 min, 40% B; Wave Length: 220 nm; RT1(min): 10.47/11.2;). Lyophilization yielded (3R,5R)-5-(3-((2- (methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (49.2 mg, 115 µmol, 18.6 %) and (3R,5S)-5-(3-((2- (methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (57.4 mg, 134 µmol, 21.6 %) as a white solid. [00343] (3R,5R)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate: m/z (ES+) [M+H] + = 428.20; HPLC tR =1.218 min.1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.12 (s, 1H), 8.31 (s, 1H), 7.59 (d, J = 37.8 Hz, 2H), 7.08 (d, J = 130.3 Hz, 1H), 6.67 (d, J = 245.9 Hz, 1H), 5.17 (s, 1H), 4.86 (s, 1H), 4.50 (s, 2H), 3.85 (d, J = 5.0 Hz, 2H), 3.35 (s, 3H), 2.69 (d, J = 14.6 Hz, 1H), 2.02 (d, J = 50.7 Hz, 1H), 1.24 (s, 3H), 0.60 (d, J = 5.1 Hz, 2H), 0.52-0.36 (m, 2H). [00344] (3R,5S)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5- yl)tetrahydrofuran-3-yl (1-methylcyclopropyl)carbamate: m/z (ES+) [M+H] + = 428.20; HPLC tR =1.306 min.1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.13 (s, 1H), 8.31 (s, 1H), 8.02- 7.14 (m, 2H), 6.92 (d, J = 6.4 Hz, 1H), 6.69 (d, J = 251.5 Hz, 1H), 5.25 (s, 1H), 5.03 (s, 1H), 4.50 (s, 2H), 4.13 (d, J = 15.7 Hz, 1H), 3.74 (d, J = 10.3 Hz, 1H), 3.36 (s, 3H), 2.30 (d, J = 24.5 Hz, 2H), 1.27 (s, 3H), 0.69-0.59 (m, 2H), 0.51 (d, J = 5.3 Hz, 2H). [00345] Additional compounds prepared according to the methods of Example 10 are depicted in Table 6 below. Table 6. Additional Exemplary Compounds
Figure imgf000642_0001
Example 11 [00346] Additional compounds set forth in Table 7 were synthesized according to the procedures described herein.
Figure imgf000643_0001
Figure imgf000644_0001
Figure imgf000645_0001
Figure imgf000646_0001
Figure imgf000647_0001
Figure imgf000648_0001
Figure imgf000649_0001
Example 12 rel-(1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate rel-(1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate
Figure imgf000650_0001
Figure imgf000651_0001
ethyl 1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxylate
Figure imgf000651_0002
[00347] Step 1. To a stirred solution ethyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5- carboxylate (1 g, 5 mmol), silver(I) trifluoromethanesulfonate(3 g, 0.01 mol), KF (0.9 g, 0.02 mol) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (3 g, 8 mmol) in Ethyl acetate (35 mL) were added 2-fluoropyridine (1 g, 0.01 mol) and trimethyl(trifluoromethyl)silane (2 g, 0.01 mol) under N2. The reaction was stirred at room temperature for overnight avoiding light. The mixture was filtered and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 55% to 60% gradient in 10 min; detector, UV 220 nm to afford ethyl 1-methyl-3- ((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxylate (1.2 g, 2.4 mmol, 40 %, 50% Purity) as a white solid. m/z (ES+) [M+H]+ =253.00; HPLC tR = 0.987 min. lithium 1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxylate
Figure imgf000652_0001
[00348] Step 2. To a stirred solution of ethyl 1-methyl-3-((trifluoromethoxy)methyl)-1H- pyrazole-5-carboxylate (1.2 g, 50% Wt, 2.4 mmol) in MeOH (10 mL) was added a solution of LiOH (85 mg, 3.6 mmol) in H2O (4 mL). The reaction was stirred at room temperature for 30 min. The mixture was concentrated and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% gradient in 8 min; detector, UV 254 nm to afford lithium 1-methyl-3-((trifluoromethoxy)methyl)-1H- pyrazole-5-carboxylate (230 mg, 1.00 mmol, 42 %) as a white solid. m/z (ES+) [M+H]+ =225.25; HPLC tR = 0.717 min. 3-(cyclopent-3-en-1-yl)-3-oxopropanenitrile
Figure imgf000652_0002
[00349] Step 3. To a mixture of CH3CN (12.00 g, 0.29 mol) in THF (200 mL) was added n-BuLi (0.14 L, 0.36 mol) drop wise at -78 °C under nitrogen atmosphere. The mixture was stirred for 2 h at -78 °C prior addition of ethyl cyclopent-3-ene-1-carboxylate (20.00 g, 0.14 mol). The mixture was stirred for 4 h at -50 °C. The reaction mixture was diluted with H2O (50 mL), then adjusted to pH 6~7 with 1M HCl, the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo resulted in 3-(cyclopent-3-en-1-yl)-3- oxopropanenitrile (27.40 g, 70%) as a yellow oil. m/z (ES+) [M+H]+=no signal in LCMS. 1-(tert-butyl)-3-(cyclopent-3-en-1-yl)-1H-pyrazol-5-amine
Figure imgf000652_0003
[00350] Step 4. A resealable reaction vial was charged with 3-(cyclopent-3-en-1-yl)-3- oxopropanenitrile (27.40 g, 203.00 mmol), tert-butylhydrazine (60.80 g, 689.00 mmol), DIEA (126.00 g, 973.00 mmol), IPA (300 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 12 h at 80 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (50.00 g column; eluting with PE/EA; ratio:10/1). Concentration in vacuo resulted in 1-(tert- butyl)-3-(cyclopent-3-en-1-yl)-1H-pyrazol-5-amine (23.00 g, 55 %) as a white solid. m/z (ES+) [M+H] + =206.20; HPLC tR = 0.398 min. benzyl (1-(tert-butyl)-3-(cyclopent-3-en-1-yl)-1H-pyrazol-5-yl) carbamate
Figure imgf000653_0001
[00351] Step 5. To a mixture of 1-(tert-butyl)-3-(cyclopent-3-en-1-yl)-1H-pyrazol-5-amine (17.60 g, 85.70 mmol) and NaHCO3 (36.00 g, 429.00 mmol) in ACN (200 mL) was added benzyl carbonochloridate (43.90 g, 257.00 mmol) drop wise at 0 °C under nitrogen atmosphere. The mixture was stirred for 12 h at 25 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40.00 g column; eluting with PE/EA; ratio:8/1). Concentration in vacuo resulted in benzyl (1-(tert-butyl)-3-(cyclopent-3-en-1- yl)-1H-pyrazol-5-yl) carbamate (25.6 g, 88.0 %) as a white solid. m/z (ES+) [M+H] + =340.15; HPLC tR = 0.950 min. benzyl (3-((1R,3s,5S)-6-oxabicyclo[3.1.0] hexan-3-yl)-1-(tert-butyl)-1H-pyrazol-5- yl)carbamate
Figure imgf000653_0002
[00352] Step 6. A resealable reaction vial was charged with benzyl (1-(tert-butyl)-3-(cyclopent- 3-en-1-yl)-1H-pyrazol-5-yl) carbamate (25.00 g, 74.00 mmol), H2O2 (36.00 g, 35% Wt, 0.37 mol), Na2WO4 (2.20 g, 7.40 mmol), PhP(O)(OH)2 (600 mg, 3.70 mmol), Me(n-C8H17)3N]HSO4 (3.40 g, 7.40 mmol), i-PrOAc (300 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 24 h at 25 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. Na2S2O3(50.00 g, 316 mmol) was added, and the mixture was stirred for 15 min at 25 °C. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (10 g column; eluting with PE/EA; ratio:4/1). Concentration in vacuo resulted in benzyl (3- ((1R,3s,5S)-6-oxabicyclo[3.1.0] hexan-3-yl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (11.00 g, 42 %) as a white solid. m/z (ES+) [M+H] + =356.20; HPLC tR = 0.917 min. benzyl (1-(tert-butyl)-3-(rac-(1R,3R,4R)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl) carbamate
Figure imgf000654_0001
[00353] Step 7. A resealable reaction vial was charged with benzyl (3-((1R,3s,5S)-6- oxabicyclo[3.1.0] hexan-3-yl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (20.00 g, 56.00 mmol), Et3N-HF (200 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 12 h at 60 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (60.00 g column; eluting with PE/EA; ratio:4/1). Concentration in vacuo resulted in benzyl (1-(tert-butyl)- 3-(rac-(1R,3R,4R)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl) carbamate (13.00 g, 62 %) as a white solid. m/z (ES+) [M+H] + =376.15; HPLC tR = 0.851 min. rac-(1S,2R,4R)-4-(5-(((benzyloxy)carbonyl) amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl 4-nitrobenzoate
Figure imgf000655_0001
[00354] Step 8. To a mixture of benzyl (1-(tert-butyl)-3-(rac-(1R,3R,4R)-3-fluoro-4- hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (13.00 g, 35.00 mmol)， 4-nitrobenzoic acid (6.90 g, 42.00 mmol) and Ph3P (21.00 g, 80.00 mmol) in THF (130 mL), DIAD (16.00 g, 80.00 mmol) was added drop wise at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at 0 °C. The mixture was stirred for 12 h at 25 °C. The reaction mixture was diluted with H2O (20 mL), then adjusted to pH 7~8 with 1M HCl. and the aqueous phase was extracted with EA (50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40.00 g column; eluting with PE/EA; ratio:4/1). Concentration in vacuo resulted in rac-(1S,2R,4R)-4-(5-(((benzyloxy)carbonyl) amino)-1-(tert-butyl)-1H-pyrazol-3-yl)- 2-fluorocyclopentyl 4-nitr obenzoate (15.80 g, 87 %) as a white solid. m/z (ES+) [M+H] + =525.35; HPLC tR = 1.294 min. benzyl (1-(tert-butyl)-3-(rac-(1R,3R,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl) carbamate
Figure imgf000655_0002
[00355] Step 9. A resealable reaction vial was charged with rac-(1S,2R,4R)-4-(5- (((benzyloxy)carbonyl) amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl 4- nitrobenzoate (15.80 g, 30.10 mmol), LiOH (90.40 mL, 1 M, 90.40 mmol), THF/MeOH (150 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 1 h at 25 °C. The residue was diluted with water, then adjusted to pH 6~7 with 1M HCl. and the aqueous phase was extracted with EA (40 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm, Concentration in vacuo resulted in benzyl (1-(tert- butyl)-3-(rac-(1R,3R,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl) carbamate (5.20 g, 46 %) as a white solid. m/z (ES+) [M+H] + =376.10; HPLC tR = 0.783 min. benzyl (1-(tert-butyl)-3-(rac-(1R,3R,4S)-3-fluoro-4-(((4-nitrophenoxy) carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate
Figure imgf000656_0001
[00356] Step 10. A resealable reaction vial was charged with benzyl (1-(tert-butyl)-3-(rac- (1R,3R,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl) carbamate (5.20 g, 14.00 mmol), DMAP (0.34 g, 2.80 mmol), Py (3.30 g, 42.00 mmol), DCM (52 mL) was added, and a stirbar before being evacuated and purged with nitrogen three times, then 4-nitrophenyl carbonochloridate (4.20 g, 21.00 mmol) was added drop wise at 0 °C and the mixture was stirred for 1 h at 25 °C. The reaction mixture was diluted with H2O (20 mL), and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (15.00 g column; eluting with PE/EA; ratio:2/1). Concentration in vacuo resulted in benzyl (1-(tert-butyl)-3-(rac-(1R,3R,4S)-3-fluoro-4-(((4-nitrophenoxy) carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (7.20 g, 96 %) as a white solid. m/z (ES+) [M+H] + =541.10; HPLC tR = 0.917 min. rac-(1S,2R,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl(1- methylcyclopropyl)carbamate
Figure imgf000656_0002
[00357] Step 11. A round bottomed flask was charged with benzyl (1-(tert-butyl)-3-(rac- (1R,3R,4S)-3-fluoro-4-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (2.00 g, 4.00 mmol), 1-methylcyclo- propan-1-amine hydrochloride (0.80 g, 7.00 mmol), DIEA (2.00 g, 0.02 mol), DMAP (0.05 g, 0.40 mmol), THF (20 mL) was added and a stirbar before being evacuated and purged with nitrogen three times, and the solution was stirred for 2 hour at 25 °C. The reaction mixture was diluted with H2O (30 mL), and the aqueous phase was extracted with EA (90 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 80% gradient in 15 min; detector, UV 254 nm, Concentration in vacuo resulted in rac-(1S,2R,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl(1- methylcyclopropyl)carbamate (1.70 g, 97 %) as a white solid. m/z (ES+) [M+H] + =473.30; HPLC tR = 0.915 min. rac-(1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (1- methylcyclopropyl) carbamate
Figure imgf000657_0001
[00358] Step 12. A stirred mixture of rac-(1S,2R,4R)-4-(5-(((benzyloxy)carbonyl) amino)-1- (tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (1-methylcyclopropyl) carbamate (1.70 g, 3.60 mmol) and Pd/C (0.11 g, 1.10 mmol) in EA (10 mL) and THF (10 mL) was treated with H2 for 2 h at 25 °C. The mixture was filtered through a Celite pad. Concentration in vacuo resulted in rac- (1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (1- methylcyclopropyl) carbamate (1.10 g, 90 %) as a white solid. m/z (ES+) [M+H] + =339.20; HPLC tR = 0.665 min. rac-(1S,2R,4R)-4-(1-(tert-butyl)-5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido) -1H-pyrazol-3-yl)-2-fluorocyclopentyl (1-methylcyclopropyl) carbamate
Figure imgf000658_0001
[00359] Step 13. To a mixture of rac-(1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl (1-methyl cyclopropyl) carbamate (140 mg, 414 µmol) in EA (2 mL) were added 1-methyl-3-((trifluoromethoxy) methyl)-1H-pyrazole-5-carboxylic acid (102 mg, 455 µmol) and DIEA (535 mg, 4.14 mmol), then T3P (4.20 g, 50% Wt, 6.62 mmol) drop wise at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h at 80 °C. The reaction mixture was diluted with H2O (15 mL), and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Prep-TLC (MeOH/DCM; ratio:1/20) to afford rac-(1S,2R,4R)-4-(1-(tert-butyl)-5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole- 5-carboxamido) -1H-pyrazol-3-yl)-2-fluorocyclopentyl (1-methylcyclopropyl) carbamate (218 mg, 96.8 %) as a yellow solid. m/z (ES+) [M+H] + =545.40; HPLC tR = 1.158 min. rel-(1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl) cyclopentyl (1-methylcyclopropyl) carbamate
Figure imgf000658_0002
[00360] Step 14. To a mixture of rac-(1S,2R,4R)-4-(1-(tert-butyl)-5-(1-methyl-3- ((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (1-methylcyclopropyl) carbamate (200 mg, 367 µmol) in FA (4 mL). The mixture was stirred for 2 h at 80 °C. The reaction mixture was diluted with H2O (15 mL), and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 15 min; detector, UV 254 nm, Concentration in rel-(1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl) cyclopentyl (1-methylcyclopropyl) carbamate (110 mg, 61.3 %) as a white solid. m/z (ES+) [M+H] + =489.15; HPLC tR =1.042 min. rel-(1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate & rel-(1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate
Figure imgf000659_0001
[00361] rac-(1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate (110 mg, 225 µmol)l was purified by chiral Pre-HPLC (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 10.5 min; Wave Length: 220/254 nm; RT1(min): 6.72; RT2(min): 8.39; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.3 mL; Number Of Runs: 10). [00362] The fraction eluting at RT1(min): 6.72 was lyophilized, yielding rel-(1S,2R,4R)-2- fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-5- yl) cyclopentyl (1-methylcyclopropyl) carbamate (26.7 mg, 49 %) as a white amorphous solid.m/z (ES+) [M+H] + =489.15; HPLC tR =1.512 min. 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 10.87 (s, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 6.43 (s, 1H), 5.11 (s, 3H), 4.99 (s, 1H), 4.09 (s, 3H), 3.22 (t, 1H), 2.68 (p, 1H), 2.41 (dd, 1H), 1.87 (dq, 2H), 1.26 (s, 3H), 0.63 (q, 2H), 0.50 (q, 2H). [00363] The fraction eluting at RT2(min): 8.39 was lyophilized, yielding rel-(1R,2S,4S)-2- fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol- 5-yl) cyclopentyl (1-methylcyclopropyl) carbamate (29.3 mg, 53 %) as a white amorphous solid. m/z (ES+) [M+H] + =489.20; HPLC tR =1.512 min.1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.86 (s, 1H), 7.64 (s, 1H), 7.29 (s, 1H), 6.44 (s, 1H), 5.11 (s, 3H), 4.91 - 4.80 (m, 1H), 4.09 (s, 3H), 3.22 (s, 1H), 2.68 (s, 1H), 2.41 (s, 1H), 2.10 - 1.76 (m, 2H), 1.26 (s, 3H), 0.62 (t, 2H), 0.50 (d, 2H).
Example 13
Additional compounds set forth in Table 8 were synthesized according to the procedures described herein.
Table 8. Additional Exemplary Compounds
Figure imgf000661_0001
Figure imgf000662_0001
Figure imgf000663_0001
Figure imgf000664_0001
Figure imgf000665_0001
Figure imgf000666_0001
Figure imgf000667_0001
Figure imgf000668_0001
Figure imgf000669_0001
Figure imgf000670_0001
Figure imgf000671_0001
Figure imgf000672_0001
Figure imgf000673_0001
Figure imgf000674_0001
Figure imgf000675_0001
Figure imgf000676_0001
Figure imgf000677_0001
Example 14 rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000678_0001
Figure imgf000679_0001
rac-benzyl (1-(tert-butyl)-3-((1R,3R,4R)-3-hydroxy-4-methoxycyclopentyl)-1H-pyrazol-5- yl)carbamate
Figure imgf000679_0002
[00364] Step 1. To a stirred solution of benzyl (3-((1R,3s,5S)-6-oxabicyclo[3.1.0]hexan-3-yl)-1- (tert-butyl)-1H-pyrazol-5-yl)carbamate (2.5 g, 1 Eq, 7.0 mmol) in MeOH (20 mL) was added conc H2SO4 (69 mg, 37 μL, 0.1 Eq, 0.70 mmol). The reaction was stirred at room temperature for overnight. The mixture was adjusted PH to 7 with NaHCO3 (aq) and extracted with DCM three times. The combined organic layers were concentrated and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 40% to 60% gradient in 10 min; detector, UV 220 nm to afford rac-benzyl (1-(tert-butyl)- 3-((1R,3R,4R)-3-hydroxy-4-methoxycyclopentyl)-1H-pyrazol-5-yl)carbamate (2.2 g, 5.7 mmol, 81 %) as colorless oil. m/z (ES+) [M+H]+ =388.40; HPLC tR = 0.792 min. rac-(1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- methoxycyclopentyl 4-nitrobenzoate
Figure imgf000679_0003
[00365] Step 2. To a stirred solution of rac-benzyl (1-(tert-butyl)-3-((1R,3R,4R)-3-hydroxy-4- methoxycyclopentyl)-1H-pyrazol-5-yl)carbamate (2.2 g, 1 Eq, 5.7 mmol) and 4-nitrobenzoic acid (1.1 g, 1.2 Eq, 6.8 mmol) in THF (25 mL) was added Ph3P (4.5 g, 3 Eq, 17 mmol) under N2. To above reaction was added DIAD (3.4 g, 3.3 mL, 3 Eq, 17 mmol) under 0 ºC. The reaction was stirred at room temperature for 3 h. The mixture was concentrated and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 70% gradient in 8 min; detector, UV 220 nm to afford rac-(1S,2R,4S)-4-(5- (((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-methoxycyclopentyl 4- nitrobenzoate (1.9 g, 3.5 mmol, 62 %) as yellow oil. m/z (ES+) [M+H]+ =537.40; HPLC tR = 1.075 min. rac-benzyl (1-(tert-butyl)-3-((1R,3S,4R)-3-hydroxy-4-methoxycyclopentyl)-1H-pyrazol-5- yl)carbamate
Figure imgf000680_0001
[00366] Step 3. To a stirred solution of (1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert- butyl)-1H-pyrazol-3-yl)-2-methoxycyclopentyl 4-nitrobenzoate (1.9 g, 1 Eq, 3.5 mmol) in MeOH/THF (10 mL) was added a solution of LiOH (0.13 g, 1.5 Eq, 5.3 mmol) in H2O (2 mL). The reaction was stirred at room temperature for 1 h. The mixture was adjusted PH to 6-7 with HCl(1 M), extracted with EA three times and concentrated. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 50% gradient in 8 min; detector, UV 220 nm to afford rac-benzyl (1-(tert-butyl)- 3-((1R,3S,4R)-3-hydroxy-4-methoxycyclopentyl)-1H-pyrazol-5-yl)carbamate (1.0 g, 2.6 mmol, 73 %) as yellow oil. m/z (ES+) [M+H]+ =388.30; HPLC tR =1.030 min. rac-benzyl (1-(tert-butyl)-3-((1S,3R,4S)-3-methoxy-4-(((4- nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate
Figure imgf000681_0001
[00367] Step 4. To a stirred solution of rac-benzyl (1-(tert-butyl)-3-((1R,3S,4R)-3-hydroxy-4- methoxycyclopentyl)-1H-pyrazol-5-yl)carbamate (1 g, 1 Eq, 3 mmol) in DCM (10 mL) was added pyridine (0.6 g, 0.6 mL, 3 Eq, 8 mmol). To above reaction was added 4-nitrophenyl carbonochloridate (0.8 g, 1.5 Eq, 4 mmol) under 0 ºC. The reaction was stirred at room temperature for overnight. The mixture was concentrated and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 60% to 100% gradient in 8 min; detector, UV 220 nm to afford rac-benzyl (1-(tert-butyl)-3-((1S,3R,4S)-3- methoxy-4-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (660 mg, 1.19 mmol, 50 %) as colorless oil. m/z (ES+) [M+H]+ =553.40; HPLC tR = 1.067 min. rac-(1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1Hpyrazol-3-yl)-2- methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000681_0002
[00368] Step 5. To a stirred solution of rac-benzyl (1-(tert-butyl)-3-((1S,3R,4S)-3-methoxy-4- (((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (660 mg, 1 Eq, 1.19 mmol) in THF (10 mL) was added DIEA (926 mg, 1.25 mL, 6 Eq, 7.17 mmol) and bicyclo[1.1.1]pentan-1-amine hydrochloride (429 mg, 3 Eq, 3.58 mmol). The reaction was stirred at room temperature for overnight. The mixture was concentrated and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 60% to 100% gradient in 10 min; detector, UV 220 nm to afford rac-(1S,2R,4S)-4-(5- (((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1Hpyrazol-3-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (400 mg, 805 μmol, 67.4 %) as yellow oil. m/z (ES+) [M+H]+ =497.40; HPLC tR = 1.186 min. rac-(1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1Hpyrazol-3-yl)-2- methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000682_0001
[00369] Step 6. A stirred mixture of rac-(1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert- butyl)-1H-pyrazol-3-yl)-2-methoxycyclopentylbicyclo[1.1.1]pentan-1-ylcarbamate (390 mg, 1 Eq, 785 μmol) and Pd/C (41.8 mg, 0.5 Eq, 393 μmol) in THF/EA (10 mL) was treated with H2 for 1 hour at room temperature. The mixture was filtered and concentrated. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 8 min; detector, UV 220 nm to afford rac-(1S,2R,4S)-4- (5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1- ylcarbamate (240 mg, 662 μmol, 84.3 %) as a white solid. m/z (ES+) [M+H]+ =363.15; HPLC tR = 0.658 min. rac-(1S,2R,4S)-4-(1-(tert-butyl)-5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000682_0002
[00370] Step 7. To a solution of rac-(1S,2R,4S)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2- methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (120 mg, 1 Eq, 331 μmol) and 3-(2,2- difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid (68.2 mg, 1 Eq, 331 μmol) in EA (5 mL) was added DIEA (214 mg, 288 μL, 5 Eq, 1.66 mmol). To above reaction was added T3P/EA (632 mg, 50% Wt, 3 Eq, 993 μmol)) at 0 ºC. The reaction was stirred at 80 °C for 2 hour. The mixture was quenched with water, filtered and extracted with EA three times. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 80% gradient in 10 min; detector, UV 254 nm to afford rac-(1S,2R,4S)- 4-(1-(tert-butyl)-5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3- yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (170 mg, 309 μmol, 93.3 %) as colorless oil. m/z (ES+) [M+H]+ =551.30; HPLC tR = 1.152 min. rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-3-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000683_0001
[00371] Step 8. rac-(1S,2R,4S)-4-(1-(tert-butyl)-5-(3-(2,2-difluoroethoxy)-1-methyl-1H- pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1- ylcarbamate (165 mg, 1 Eq, 300 μmol) was dissolved in FA (5 mL). The reaction was stirred at 80 °C for 1 hour. The mixture was concentrated and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 60% to 80% gradient in 8 min; detector, UV 254 nm to afford rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1- methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (130 mg, 263 μmol, 87.7 %) as a white solid. m/z (ES+) [M+H]+ =495.40; HPLC tR = 0.817 min. rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000684_0001
[00372] The rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-methoxycyclopentylbicyclo[1.1.1]pentan-1-ylcarbamate (130 mg, 1 Eq, 263 μmol) was purified by Prep-chiral-HPLC(Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1-- HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 11 min; Wave Length: 220/254 nm; RT1(min): 6.98; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.3 mL; Number Of Runs: 9). Lyophilization yielded rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H- pyrazole-5-carboxamido)-1H-pyrazol-5-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1- ylcarbamate (35.8 mg, 71.5 μmol, 54 %, 98.8% Purity) as a white amorphous solid. m/z (ES+) [M+H]+ =495.25; HPLC tR = 1.248 min. 1H NMR (400 MHz, DMSO-d6) 12.22 (s, 1H), 10.72 (s, 1H), 7.87 (s, 1H), 6.64 (s, 1H), 6.52-6.22 (m, 2H), 4.96 (s, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.72 (q, J = 6.1, 5.6 Hz, 1H), 3.26 (s, 3H), 3.10 (d, J = 10.0 Hz, 1H), 2.42-2.26 (m, 3H), 1.91 (s, 6H), 1.74 (s, 2H). [00373] The rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-methoxycyclopentylbicyclo[1.1.1]pentan-1-ylcarbamate (130 mg, 1 Eq, 263 μmol) was purified by Prep-chiral-HPLC(Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1-- HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 11 min; Wave Length: 220/254 nm; RT2(min): 8.70; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.3 mL; Number Of Runs: 9). Lyophilization yielded rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H- pyrazole-5-carboxamido)-1H-pyrazol-5-yl)-2-methoxycyclopentyl bicyclo[1.1.1]pentan-1- ylcarbamate (37.3 mg, 75.0 μmol, 57 %, 99.4% Purity) as a white amorphous solid. m/z (ES+) [M+H]+ =495.20; HPLC tR = 0.826 min.1H NMR (400 MHz, DMSO-d6) 12.22 (s, 1H), 10.72 (s, 1H), 7.88 (s, 1H), 6.64 (s, 1H), 6.53-6.20 (m, 2H), 4.96 (s, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.72 (q, J = 6.2, 5.6 Hz, 1H), 3.26 (s, 3H), 3.11 (d, J = 9.9 Hz, 1H), 2.45-2.23 (m, 3H), 1.91 (s, 6H), 1.74 (s, 2H). Example 15 rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-hydroxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-hydroxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000685_0001
Figure imgf000686_0001
rac-(1R,2R,4R)-4-(5- (((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- hydroxycyclopentyl acetate
Figure imgf000686_0002
[00374] Step 1. A round bottom flask was charged with benzyl (3-((1R,3s,5S)-6- oxabicyclo[3.1.0]hexan-3-yl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (1 g, 3 mmol), BF3OEt2 (0.6 g, 4 mmol), AcOH (10 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the solution was stirred for 2 h at 0 °C. The solution was quenched with sat.NH4Cl. The solution was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 60% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1R,2R,4R)-4-(5- (((benzyloxy)carbonyl)amino)-1- (tert-butyl)-1H-pyrazol-3-yl)-2-hydroxycyclopentyl acetate (950 mg, 80 %) as a white solid. m/z (ES+) [M+H] + =416.40; HPLC tR = 0.825 min. rac-(1S,2R,4S)-2-acetoxy-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3- yl)cyclopentyl 4-nitrobenzoate
Figure imgf000687_0002
[00375] Step 2. To a mixture of rac-(1R,2R,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert- butyl)-1H-pyrazol-3-yl)-2-hydroxycyclopentyl acetate (0.95 g, 2.29 mmol), 4-nitrobenzoic acid (459 mg, 2.74 mmol) and PPh3 (1.38 g, 5.26 mmol) in THF (10 mL) was added DIAD (1.06 g, 5.26 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at 0 °C. The mixture was stirred for another 12 h at 25 °C. The reaction mixture was diluted with H2O (60 mL), and the aqueous phase was extracted with EA (90 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1S,2R,4S)-2-acetoxy-4-(5-(((benzyloxy)carbonyl)amino)- 1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl 4-nitrobenzoate (1.16 g, 89.9 %) as a yellow solid. m/z (ES+) [M+H] + =565.40; HPLC tR = 1.278 min. rac-benzyl (1-(tert-butyl)-3-((1r,3R,4S)-3,4-dihydroxycyclopentyl)-1H-pyrazol-5- yl)carbamate
Figure imgf000687_0001
[00376] Step 3. A round bottom flask was charged with rac-(1S,2R,4S)-2-acetoxy-4-(5- (((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl 4-nitrobenzoate (1.16 g, 2.05 mmol), LiOH (3.08 mL, 1M, 3.08 mmol), MeOH/THF (12 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the solution was stirred for 1 h at 25 °C. The residue was diluted with water, then adjusted to pH 7~8 with 1 M HCl, and the aqueous phase was extracted with EA (150 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 70% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-benzyl (1-(tert-butyl)-3-((1r,3R,4S)-3,4-dihydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (0.56 g, 73.0 %) as a white solid. m/z (ES+) [M+H] + =374.40; HPLC tR = 0.725 min. rac-benzyl (1-(tert-butyl)-3-((1S,3S,4R)- 3-((tert-butyldiphenylsilyl)oxy)-4- hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate
Figure imgf000688_0001
[00377] Step 4. To a mixture of rac-benzyl (1-(tert-butyl)-3-((1r,3R,4S)-3,4- dihydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (460 mg, 1.23 mmol) and 1-methylimidazole (607 mg, 7.39 mmol) in DCM (5 mL) was added TBDPSCl (675 mg, 2.46 mmol) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 5 h at 25 °C. The reaction mixture was diluted with H2O (30 mL), and the aqueous phase was extracted with EA (60 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-benzyl (1-(tert-butyl)-3- ((1S,3S,4R)- 3-((tert-butyldiphenylsilyl)oxy)-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (765 mg, 91 %) as a white solid. m/z (ES+) [M+H] + =612.50; HPLC tR = 1.486 min. rac-benzyl (1-(tert-butyl)-3-((1R,3R,4S)-3- ((tert-butyldiphenylsilyl)oxy)-4-(((4- nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate
Figure imgf000688_0002
[00378] Step 5. To a mixture of rac-benzyl (1-(tert-butyl)-3-((1R,3R,4S)-3-((tert- butyldiphenylsilyl)oxy)-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (800 mg, 1.31 mmol), DMAP( 32 mg, 0.26 mmol) and pyridine (310 mg, 3.92 mmol) in THF (9 mL) was added 4- nitrophenyl carbonochloridate (527 mg, 2.61 mmol) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 4 h at 25 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-benzyl (1-(tert-butyl)-3-((1R,3R,4S)-3- ((tert- butyldiphenylsilyl)oxy)-4-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5- yl)carbamate (820 mg, 80.7 %) as a yellow solid. m/z (ES+) [M+H] + =777.60; HPLC tR = 1.572 min. rac-(1S,2R,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-((tert- butyldiphenylsilyl)oxy)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000689_0001
[00379] Step 6. A resealable reaction vial was charged with rac-benzyl (1-(tert-butyl)-3- ((1R,3R,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)- 1H-pyrazol-5-yl)carbamate (800 mg, 1.03 mmol), bicyclo[1.1.1]pentan-1-amine hydrochloride (246 mg, 2.06 mmol), DMAP (12.6 mg, 0.10 mmol), DIEA (665 mg, 5.15 mmol), THF (10 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 1 h at 25 °C. The reaction concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1S,2R,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-((tert- butyldiphenylsilyl)oxy)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (600 mg, 80.8 %)as a white solid. m/z (ES+) [M+H] + =721.65; HPLC tR = 1.092 min. rac-(1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-((tert- butyldiphenylsilyl)oxy)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000690_0001
[00380] Step 7. A stirred mixture of rac-(1S,2R,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert- butyl)-1H-pyrazol-3-yl)-2-((tertbutyldiphenylsilyl)oxy)cyclopentyl bicyclo[1.1.1]pentan-1- ylcarbamate (780 mg, 1.08 mmol) and Pd/C (11.5 mg, 0.11 mmol) in THF/EA (10 mL) was treated with H2 for 1 h at 25 °C. The reaction mixture was filtered through a pad of Celite, the pad was washed with EA, and the filtrate was concentrated in vacuo. Concentration in vacuo resulted in rac-(1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-((tert- butyldiphenylsilyl)oxy)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (470 mg, 74.0 %) as a white solid. m/z (ES+) [M+H] + =587.55; HPLC tR = 1.244 min. rac-(1S,2R,4R)-4-(1-(tert-butyl)-5-(3-(2,2-difluoroethoxy)-1-methyl-1Hpyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000690_0002
[00381] Step 8. To a mixture of rac-(1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2- ((tert-butyldiphenylsilyl)oxy)cyclopentylbicyclo[1.1.1]pentan-1-ylcarbamate (450 mg, 0.77 mmol), DIEA (991 mg, 7.67 mmol) and 3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5- carboxylic acid (174 mg, 0.84 mmol) in EA (10 mL) was added T3P (3.90 g, , 50% Wt, 6.13 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h at 80 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (20 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-TLC (PE/EA; ratio:20/1) to afford rac-(1S,2R,4R)-4-(1-(tert-butyl)-5-(3-(2,2-difluoroethoxy)-1-methyl-1Hpyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (500 mg, 84.1 %) as an orange solid. m/z (ES+) [M+H] + =775.60; HPLC tR = 1.519 min. rac-(1R,2S,4S)-2-((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)-4-(5-(3-(2,2-difluoroethoxy)-1- methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl formate
Figure imgf000691_0001
[00382] Step 9. A resealable reaction vial was charged with rac-(1S,2R,4R)-4-(1-(tert-butyl)-5- (3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2-((tert- butyldiphenylsilyl)oxy) cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (450 mg, 0.58 mmol), FA (3 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 3 h at 80°C. The reaction was concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1R,2S,4S)-2-((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)- 4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3- yl)cyclopentyl formate (190 mg, 64.4 %) as a white solid. m/z (ES+) [M+H] + =509.30; HPLC tR = 1.036 min. rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1Hpyrazole-5-carboxamido)-1H- pyrazol-3-yl)-2 hydroxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000692_0002
[00383] Step 10. A resealable reaction vial was charged with rac-(1R,2S,4S)-2- ((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole- 5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl formate (180 mg, 354 μmol), LiOH (0.35 mL, 1M, 354 μmol), THF/MeOH (3 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 1 h at 25 °C. The reaction was concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. Lyophilization yielded rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1Hpyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2 hydroxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (160 mg, 94.1%) as a white solid. m/z (ES+) [M+H] + =481.30; HPLC tR = 0.953 min. rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-hydroxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-hydroxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000692_0001
[00384] Step 11. Rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-hydroxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (130 mg, , 271 μmol) was purified by chiral Pre-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1-- HPLC; Flow rate: 20 mL/min; Gradient: 90% B to 90% B in 30 min; Wave Length: 220/254 nm; RT1(min): 3.44; RT2(min): 14.45; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 2.4 mL; Number Of Runs: 1). Lyophilization yielded rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethoxy)- 1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-5-yl)-2-hydroxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (42.1 mg, 65 %) as a white amorphous solid. m/z (ES+) [M+H] + =481.25; HPLC tR = 1.418 min.1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.72 (s, 1H), 7.77 (s, 1H), 6.64 (s, 1H), 6.54 - 6.19 (m, 2H), 4.78 (dd, 2H), 4.37 (td, 2H), 4.08 - 4.00 (m, 1H), 3.95 (s, 3H), 3.09 - 3.01 (m, 1H), 2.44 - 2.21 (m, 3H), 1.92 (s, 6H), 1.72 (d, 2H). [00385] Rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)- 1H-pyrazol-3-yl)-2-hydroxycyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (130 mg, 271 μmol) was purified by chiral Pre-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 90% B to 90% B in 30 min; Wave Length: 220/254 nm; RT1(min): 3.44; RT2(min): 14.45; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 2.4 mL; Number Of Runs: 1). Lyophilization yielded rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H- pyrazole-5-carboxamido)-1H-pyrazol-5-yl)-2-hydroxycyclopentyl bicyclo[1.1.1]pentan-1- ylcarbamate (43.2 mg, 66 %) as a white amorphous solid . m/z (ES+) [M+H] + =481.20; HPLC tR =1.418 min.1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.72 (s, 1H), 7.77 (s, 1H), 6.64 (s, 1H), 6.55 - 6.19 (m, 2H), 4.78 (dd, 2H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 4.08 - 3.99 (m, 1H), 3.95 (s, 3H), 3.10 - 3.01 (m, 1H), 2.39 - 2.22 (m, 3H), 1.92 (s, 6H), 1.72 (d, 2H). Example 16 rel-(1R,2S,4S)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H- pyrazol-5-yl)cyclopentyl isopropylcarbamate rel-(1S,2R,4R)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H- pyrazol-5-yl)cyclopentyl isopropylcarbamate
Figure imgf000694_0001
Figure imgf000695_0002
rac-benzyl (1-(tert-butyl)-3-((1S,3S,4S)-3-fluoro-4-hydroxycyclopentyl)-1Hpyrazol-5- yl)carbamate
Figure imgf000695_0001
[00386] Step 1. A round bottom flask was charged with benzyl (3-((1R,3s,5S)-6- oxabicyclo[3.1.0]hexan-3-yl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (8.00 g, 0.02 mol), Et3N- 3HF (80 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 12 h at 60 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 100% gradient in 10 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-benzyl (1-(tert-butyl)-3-((1S,3S,4S)-3-fluoro-4- hydroxycyclopentyl)-1Hpyrazol-5-yl)carbamate (6.00 g, 70 %) as a white solid. m/z (ES+) [M+H] + =376.20; HPLC tR = 1.042 min. rac-(1R,2S,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl 4-nitrobenzoate
Figure imgf000696_0001
[00387] Step 2. To a mixture of rac-benzyl (1-(tert-butyl)-3-((1S,3S,4S)-3-fluoro-4- hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (6.00 g, 0.02 mol) and 4-nitrobenzoic acid (3.00 g, 0.02 mol), Ph3P (10.00 g, 0.04 mol) in THF (60 mL) was added DIAD (7.00 g, 0.04 mol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at 0 °C. The mixture was stirred for another 12 h at 25 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 100% gradient in 10 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1R,2S,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert- butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl 4-nitrobenzoate (7.60 g, 90 %) as a white solid. m/z (ES+) [M+H] + =525.25; HPLC tR = 1.332 min. rac-benzyl (1-(tert-butyl)-3-((1S,3S,4R)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5- yl)carbamate
Figure imgf000696_0002
[00388] Step 3. A round bottom flask was charged with rac-(1R,2S,4S)-4-(5- (((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl 4- nitrobenzoate (7.60 g, 14.00 mmol), LiOH (43 mL, 1 M, 43.00 mmol), THF/MeOH (80 mL) and a stirbar before being evacuated and purged with nitrogen three times. The mixture was stirred for 1 h at 25 °C. The reaction mixture was diluted with H2O (50 mL), the pH value of the solution was adjusted to 6~8 with 1 M HCl, and the aqueous phase was extracted with EA (50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 90% gradient in 15 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-benzyl (1-(tert-butyl)-3- ((1S,3S,4R)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (3.68 g, 68 %) as a white solid. m/z (ES+) [M+H] + =376.20; HPLC tR = 1.012 min. rac-benzyl (1-(tert-butyl)-3-((1S,3R,4S)-3-((tertbutyldimethylsilyl) oxy)-4- fluorocyclopentyl)-1H-pyrazol-5-yl)carbamate
Figure imgf000697_0001
[00389] Step 4. To a mixture of rac-benzyl (1-(tert-butyl)-3-((1S,3S,4R)-3-fluoro-4- hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (4.10 g, 11.00 mmol) and 1H-imidazole (5.40 g, 66.00 mmol) in DMF (50 mL) was added tert-butylchlorodimethylsilane (6.60 g, 44.00 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h at 25 °C. The reaction was concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-benzyl (1-(tert-butyl)-3-((1S,3R,4S)-3-((tertbutyldimethylsilyl) oxy)-4-fluorocyclopentyl)-1H-pyrazol- 5-yl)carbamate (4.60 g, 86 %) as a white solid. m/z (ES+) [M+H] + =409.30; HPLC tR = 1.502min. rac-1-(tert-butyl)-3-((1S,3R,4S)-3-((tert-butyldimethylsilyl)oxy)-4-fluorocyclopentyl)-1H- pyrazol-5-amine
Figure imgf000697_0002
[00390] Step 5. A stirred mixture of rac-benzyl (1-(tert-butyl)-3-((1S,3R,4S)-3-((tert- butyldimethylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)carbamate (4.60 g, 9.40 mmol) and Pd/C (0.10 g, 0.94 mmol) in THF/EA (40 mL) was treated with H2 for 1 h at 25 °C. The reaction mixture was filtered through a pad of Celite, the pad was washed with EA, and the filtrate was concentrated in vacuo. This resulted in rac-1-(tert-butyl)-3-((1S,3R,4S)-3-((tert- butyldimethylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-amine (3.10 g, 93 %) as a white solid. m/z (ES+) [M+H] + =356.20; HPLC tR = 1.358 min. rac-N-(1-(tert-butyl)-3-((1S,3R,4S)-3-((tertbutyldimethylsilyl)oxy)-4-fluorocyclopentyl)- 1H-pyrazol-5-yl)-2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-amine
Figure imgf000698_0001
[00391] Step 6. To a mixture of rac-1-(tert-butyl)-3-((1S,3R,4S)-3-((tert- butyldimethylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-amine (1.00 g, 3.00 mmol) in DMF (10 mL) was added NaH (0.40 g, 60% Wt, 0.01 mol) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 5 min at 0 °C prior to addition of 4-chloro-2- (methoxymethyl)pyrazolo[1,5-a]pyrazine (1.50 g, 6.00 mmol). The mixture was stirred for 8 h at 25 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-N-(1-(tert-butyl)-3-((1S,3R,4S)-3-((tertbutyldimethylsilyl)oxy)-4-fluorocyclopentyl)-1H- pyrazol-5-yl)-2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-amine (0.60 g, 40%) as a white solid. m/z (ES+) [M+H] + =517.25; HPLC tR = 1.428 min. rac-(1R,2S,4S)-4-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4- yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentan-1-ol
Figure imgf000699_0001
[00392] Step 7. A resealable reaction vial was charged with rac-N-(1-(tert-butyl)-3-((1S,3R,4S)- 3-((tert-butyldimethylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)-2- (methoxymethyl)pyrazolo[1,5-a]pyrazin-4-amine (1.00 g, 2.00 mmol), 4-methylbenzenesulfonic acid (0.40 g, 2.00 mmol), MeCN (10 mL) and a stirbar before being evacuated and purged with nitrogen three times. The mixture was stirred for 1 h at 25 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1R,2S,4S)-4-(1-(tert- butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)-2- fluorocyclopentan-1-ol (0.60 g, 80 %) as a white solid. m/z (ES+) [M+H] + =403.20; HPLC tR = 0.822 min. rac-(1R,2S,4S)-4-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4- yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (4-nitrophenyl) carbonate
Figure imgf000699_0002
[00393] Step 8. To a mixture of rac-(1R,2S,4S)-4-(1-(tert-butyl)-5-((2- (methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentan-1- ol (580 mg, 1.44 mmol), Py (342 mg, 4.32 mmol) and DMAP (35 mg, 0.29 mmol) in DCM (10 mL) was added 4-nitrophenyl carbonochloridate (436 mg, 2.16 mmol) in 10 mL of DCM dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at 25 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1R,2S,4S)-4-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)- 1H-pyrazol-3-yl)-2-fluorocyclopentyl (4-nitrophenyl) carbonate (700 mg, 85.6 %) as a white solid. m/z (ES+) [M+H] + =568.25; HPLC tR = 1.202 min. rac-(1R,2S,4S)-4-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4- yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl isopropylcarbamate
Figure imgf000700_0001
[00394] Step 9. A resealable reaction vial was charged with rac-(1R,2S,4S)-4-(1-(tert-butyl)-5- ((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (4-nitrophenyl) carbonate (300 mg, , 0.53 mmol), propan-2-amine (63 mg, 1.06 mmol), DIEA (342 mg, 2.64 mmol), THF (5 mL) and a stirbar before being evacuated and purged with nitrogen three times. The mixture was stirred for 1 h at 25 °C. The reaction concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1R,2S,4S)-4-(1-(tert-butyl)-5-((2- (methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl isopropylcarbamate (270 mg, 90%) as a white solid. m/z (ES+) [M+H] + =488.50; HPLC tR = 0.969 min. rac-(1R,2S,4S)-2-fluoro-4-(5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H- pyrazol-3-yl)cyclopentyl isopropylcarbamate
Figure imgf000701_0002
[00395] Step 10. A resealable reaction vial was charged with rac-(1R,2S,4S)-4-(1-(tert-butyl)-5- ((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl isopropylcarbamate (270 mg, 0.55 mmol), FA (5 mL) and a stirbar before being evacuated and purged with nitrogen three times. The mixture was stirred for 2 h at 80 °C. The reaction concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1R,2S,4S)-2-fluoro-4- (5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (150 mg, 62.8 %) as a white solid. m/z (ES+) [M+H] + =432.35; HPLC tR = 0.836 min. rel-(1R,2S,4S)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H- pyrazol-5-yl)cyclopentyl isopropylcarbamate rel-(1S,2R,4R)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H- pyrazol-5-yl)cyclopentyl isopropylcarbamate
Figure imgf000701_0001
[00396] Step 11. Rac-(1R,2S,4S)-2-fluoro-4-(5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4- yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (150 mg, 0.35 mmol) was purified by chiral Pre-HPLC (Column: CHIRALPAK IE, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 65% B to 65% B in 11.5 min; Wave Length: 220/254 nm; RT1(min): 6.26; RT2(min): 8.13; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.3 mL; Number Of Runs: 11). Lyophilization resulted in rel-(1R,2S,4S)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1,5- a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (45.8 mg, 61 %) as a white amorphous solid. m/z (ES+) [M+H] + =432.25; HPLC tR = 0.892 min.1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 9.97 (s, 1H), 8.02 (s, 1H), 7.39 (d, , 1H), 7.26 (d, Hz, 2H), 6.66 (s, 1H), 5.17 - 4.97 (m, 1H), 4.91 - 4.81 (m, 1H), 4.56 (s, 2H), 3.61 (dq, 1H), 3.32 (s, 3H), 3.22 (s, 1H), 2.51 (s, 1H), 2.49 (s, 1H), 1.88 (q, 2H), 1.06 (dd, 6H). [00397] Rac-(1R,2S,4S)-2-fluoro-4-(5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4- yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (150 mg, 0.35 mmol) was purified by chiral Pre-HPLC (Column: CHIRALPAK IE, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 65% B to 65% B in 11.5 min; Wave Length: 220/254 nm; RT1(min): 6.26; RT2(min): 8.13; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.3 mL; Number Of Runs: 11). Lyophilization resulted in rel-(1S,2R,4R)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1,5- a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (38.2 mg, 51 %) as a white amorphous solid. m/z (ES+) [M+H] + =432.20; HPLC tR =0.892 min. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 9.99 (s, 1H), 8.02 (s, 1H), 7.39 (d, 1H), 7.26 (d, 2H), 6.65 (s, 1H), 5.07 (d, 1H), 4.91 - 4.81 (m, 1H), 4.56 (s, 2H), 3.61 (dq, 1H), 3.32 (s, 3H), 3.23 (d, 1H), 2.51 (s, 1H), 2.41 (s, 1H), 1.88 (d, 2H), 1.06 (dd, 6H). Example 17 rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000703_0001
rac-benzyl (1-(tert-butyl)-3-((1S,3R,4R)-3-hydroxy-4-methylcyclopentyl)-1H-pyrazol-5- yl)carbamate
Figure imgf000703_0002
[00398] Step 1. A mixture of CuI (13.00 g, 68.00 mmol) was covered with dry THF (30 mL), and the reaction was cooled to -20 °C. After a few minutes, a solution of methylmagnesiumchloride (5.6 mL, 3 molar in THF, 17.00 mmol) was added to the reaction over approximately 3 h. The temperature of the external bath was carefully maintained between -20 and -25 °C during the addition. The reaction was stirred at -25 °C for 20 min, and a solution of benzyl (3-((1R,3s,5S)-6- oxabicyclo[3.1.0]hexan-3-yl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (1.50 g, 4.20 mmol) in THF (20 mL) was added. The mixture was stirred for 2 hour at -18 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (120 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 60% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-benzyl (1-(tert-butyl)-3- ((1S,3R,4R)-3-hydroxy-4-methylcyclopentyl)-1H-pyrazol-5-yl)carbamate (1.20 g, 77 %) as a yellow solid. m/z (ES+) [M+H] + =372.10; HPLC tR = 0.862 min. rac-(1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- methylcyclopentyl 4-nitrobenzoate
Figure imgf000704_0001
[00399] Step 2. To a mixture of rac-benzyl (1-(tert-butyl)-3-((1S,3R,4R)-3-hydroxy-4- methylcyclopentyl)-1H-pyrazol-5-yl)carbamate (1.49 g, 4.01 mmol), 4-nitrobenzoic acid (0.80 g, 4.81 mmol) and PPh3 (2.42 g, 9.23 mmol) in THF (15 mL) was added DIAD (1.87 g, 9.23 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at 0 °C. The mixture was stirred for 6 h at 25 °C. The reaction mixture was diluted with H2O (30 mL), and the aqueous phase was extracted with EA (90 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- methylcyclopentyl 4-nitrobenzoate (1.60 g, 77 %) as a yellow solid. m/z (ES+) [M+H] + =521.25; HPLC tR = 1.158 min. rac-benzyl (1-(tert-butyl)-3-((1S,3S,4R)-3-hydroxy-4-methylcyclopentyl)-1H-pyrazol-5- yl)carbamate
Figure imgf000705_0001
[00400] Step 3. A round bottomed flask was charged with rac-(1S,2R,4S)-4-(5- (((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-methylcyclopentyl 4- nitrobenzoate (1.60 g, 3.10 mmol), LiOH (4.60 mL, 1 M, 4.60 mmol), THF/MeOH (20 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the solution was stirred for 1 h at 25 °C. The residue was diluted with water (30 mL), then adjusted to pH 6~7 with 1 M HCl, and the aqueous phase was extracted with EA (90 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 60% to 90% gradient in 20 min; detector, UV 254 nm, Concentration in vacuo resulted in rac-benzyl (1-(tert-butyl)-3-((1S,3S,4R)-3-hydroxy-4- methylcyclopentyl)-1H-pyrazol-5-yl)carbamate (0.90 g, 79 %) as a yellow solid. m/z (ES+) [M+H] + =372.30; HPLC tR = 1.111 min. rac-benzyl (1-(tert-butyl)-3-((1S,3R,4S)-3-methyl-4-(((4- nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate
Figure imgf000705_0002
[00401] Step 4. To a mixture of rac-benzyl (1-(tert-butyl)-3-((1S,3S,4R)-3-hydroxy-4- methylcyclopentyl)-1H-pyrazol-5-yl)carbamate (292.00 mg, 0.79 mmol) and pyridine (187.00 mg, 2.36 mmol) in THF (3 mL) was added 4-nitrophenyl carbonochloridate (317.00 mg, 1.57 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 hour at 50 °C. Concentration in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 90% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-benzyl (1-(tert-butyl)-3- ((1S,3R,4S)-3-methyl-4-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5- yl)carbamate (200.00 mg, 47.4 %) as a white solid. m/z (ES+) [M+H] + =537.40; HPLC tR = 1.319 min. rac-(1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000706_0001
[00402] Step 5. A round bottomed flask was charged with rac-benzyl (1-(tert-butyl)-3- ((1S,3R,4S)-3-methyl-4-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5- yl)carbamate (580.00 mg, 1.08 mmol), bicyclo[1.1.1]pentan-1-amine hydrochloride (259.00 mg, 2.16 mmol), DIEA (838.00 mg, 6.49 mmol) and DMAP (66.00 mg, 0.54 mmol), THF (6 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the solution was stirred for 1.5 hour at 25 °C. The reaction mixture was diluted with H2O (30 mL), and the aqueous phase was extracted with EA (90 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 80% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (409.00 mg, 78.7 %) as a white solid. m/z (ES+) [M+H] + =481.35; HPLC tR = 0.965 min. rac-(1S,2R,4S)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000707_0001
[00403] Step 6. A stirred mixture of rac-(1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert- butyl)-1H-pyrazol-3-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (390.00 mg, 0.81 mmol) and Pd/C (17.30 mg, 0.16 mmol) in EA/THF (5 mL) was treated with H2 for 2 hour at 25 °C. The mixture was filtered through a Celite pad. The solid was filtered out. The filtrate was concentrated under vacuum. Concentration in vacuo resulted in rac-(1S,2R,4S)-4-(5-amino-1- (tert-butyl)-1H-pyrazol-3-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (260.00 mg, 92.5 %) as a pink solid. m/z (ES+) [M+H] + =347.15; HPLC tR = 0.700 min. rac-(1S,2R,4S)-4-(1-(tert-butyl)-5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000707_0002
[00404] Step 7. To a mixture of rac-(1S,2R,4S)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2- methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (250.00 mg, 0.72 mmol), [2213-076] 3- (2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid (179.00 mg, 0.87 mmol) and DIEA (933.00 mg, 7.22 mmol) in EA (10 mL) was added T3P (3.67 g, 50% Wt, 5.77 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 12 hour at 25 °C. The reaction mixture was diluted with H2O (15 mL), and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 40% to 70% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1S,2R,4S)-4-(1-(tert- butyl)-5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2- methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (350.00 mg, 90.7 %) as a yellow solid. m/z (ES+) [M+H] + =535.30; HPLC tR = 0.892 min. rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-3-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000708_0002
[00405] Step 8. A round bottomed flask was charged with rac-(1S,2R,4S)-4-(1-(tert-butyl)-5-(3- (2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2- methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (320.00 mg, 0.60 mmol), FA (4 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the solution was stirred for 2 hour at 80 °C. Concentration in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 40% to 70% gradient in 20 min; detector, UV 254 nm, Concentration in vacuo resulted in rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol- 3-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (220.00 mg, 76.8 %) as a yellow oil. m/z (ES+) [M+H] + =479.60; HPLC tR = 0.650 min. rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000708_0001
[00406] Step 9. rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (220 mg, 0.46 mmol)l was purified by chiral Pre-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1-- HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 8 min; Wave Length: 220/254 nm; RT1(min): 3.71; RT2(min): 6.13; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.5 mL; Number Of Runs: 6). Lyophilization yielded rel-(1R,2S,4R)-4-(3-(3-(2,2- difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-5-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (73.4 mg, 66.7 %) as a white amorphous solid. m/z (ES+) [M+H] + =479.20; HPLC tR = 1.352 min. 1H NMR (400 MHz, DMSO-d6) 12.21 (s, 1H), 10.70 (s, 1H), 7.74 (s, 1H), 6.64 (s, 1H), 6.53 - 6.19 (m, 2H), 4.93 (s, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.12 (s, 1H), 2.43 (s, 1H), 2.34 (s, 1H), 2.12 (s, 2H), 1.90 (s, 6H), 1.66 (s, 1H), 1.48 (s, 1H), 0.96 (s, 3H). [00407] rac-(1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxamido)- 1H-pyrazol-3-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (220 mg, 0.46 mmol)l was purified by chiral Pre-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 8 min; Wave Length: 220/254 nm; RT1(min): 3.71; RT2(min): 6.13; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.5 mL; Number Of Runs: 6). Lyophilization yielded rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H- pyrazole-5-carboxamido)-1H-pyrazol-5-yl)-2-methylcyclopentyl bicyclo[1.1.1]pentan-1- ylcarbamate (65.8 mg, 59.8 %) as a white amorphous solid. m/z (ES+) [M+H] + =479.25; HPLC tR = 1.362 min.1H NMR (400 MHz, DMSO-d6) 12.21 (s, 1H), 10.70 (s, 1H), 7.74 (s, 1H), 6.64 (s, 1H), 6.51 - 6.17 (m, 2H), 4.93 (s, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.12 (s, 1H), 2.45 (s, 1H), 2.34 (s, 1H), 2.12 (s, 2H), 1.90 (s, 6H), 1.67 (s, 1H), 1.46 (s, 1H), 0.96 (s, 3H). Example 18 rel-(1R,2R,4S)-2-fluoro-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5- yl)cyclopentyl (1-methylcyclopropyl)carbamate rel-(1S,2S,4R)-2-fluoro-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5- yl)cyclopentyl (1-methylcyclopropyl)carbamate
Figure imgf000710_0001
rac-ethyl (1R,3S,4S)-3-fluoro-4-hydroxycyclopentane-1-carboxylate
Figure imgf000711_0001
[00408] Step 1. A round bottom flask was charged with rac-ethyl (1R,3R,5S)-6- oxabicyclo[3.1.0]hexane-3-carboxylate (27.00 g, 0.17 mol), Et3N-3HF (200 mL) and a stirbar was added before being evacuated and purged with nitrogen three times, and the mixture was stirred for 12 h at 110 ºC. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This resulted in rac-ethyl (1R,3S,4S)-3-fluoro-4-hydroxycyclopentane-1-carboxylate (26.70 g, crude) as an orange oil. m/z (ES+) [M+H] + =177.10; HPLC tR = 0.786 min. rac-ethyl (1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentane-1-carboxylate
Figure imgf000711_0002
[00409] Step 2. To a mixture of rac-ethyl (1R,3S,4S)-3-fluoro-4-hydroxycyclopentane-1- carboxylate (26.70 g, 152.00 mmol) and 1-Methylimidazole (16.00 g, 197.00 mmol) in DCM (300 mL) was added tert-butylchlorodiphenylsilane (50.00 g, 182.00 mmol) in 20 mL DCM dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 12 h at 25 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with DCM (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (100 g column; eluting with PE/EA; ratio:10/1). Concentration in vacuo resulted in rac-ethyl (1R,3S,4S)- 3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentane-1-carboxylate (27.35 g, 43.5 %) as a white solid. m/z (ES+) [M+H] + =415.25; HPLC tR = 1.544 min. rac-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-3-oxopropanenitrile
Figure imgf000712_0002
[00410] Step 3. To a mixture of CH3CN (5.42 g, 131.90 mmol) in THF (300 mL) was added n- butyllithium (412 mL, 164.9 mmol) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred for 1 h at -78 °C prior addition of rac-ethyl (1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)- 4-fluorocyclopentane-1-carboxylate (27.35 g, 65.97 mmol). The mixture was stirred for 4 h at - 78 °C. The solution was diluted with water, then adjusted to pH 6~7 with 1M HCl, and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This resulted in crude rac-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-3-oxopropanenitrile (31.47 g, crude) as an orange oil. m/z (ES+) [M+H] + =410.00; HPLC tR = 1.398 min. rac-1-(tert-butyl)-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-1H- pyrazol-5-amine rac-1-(tert-butyl)-3-((1S,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-1H- pyrazol-5-amine
Figure imgf000712_0001
[00411] Step 4. A round bottom flask was charged with rac-3-((1R,3S,4S)-3-((tert- butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-3-oxopropanenitrile (31.47 g, 76.83 mmol), Tert- ButylhydrazineHydrochloride (32.55 g, 261.20 mmol), DIPEA (47.67 g, 368.80 mmol), IPA (320 mL) and a stir bar before being evacuated and purged with nitrogen three times, and the mixture was stirred for 12 h at 80 °C. The reaction was concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in a mixture of rac-1-(tert-butyl)-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4- fluorocyclopentyl)-1H-pyrazol-5-amine and rac-1-(tert-butyl)-3-((1S,3S,4S)-3-((tert- butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-amine (26.00 g, 71 %) as a colorless oil. m/z (ES+) [M+H] + =480.40; HPLC tR = 1.186 min, 1.208 min. rac-N-(1-(tert-butyl)-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)- 1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide rac-N-(1-(tert-butyl)-3-((1S,3S,4S)-3-((tert-butyldiphenylsilyl) oxy)-4-fluorocyclopentyl)- 1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide
Figure imgf000713_0001
[00412] Step 5. To a solution of a mixture of rac-1-(tert-butyl)-3-((1R,3S,4S)-3-((tert- butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-amine and rac-1-(tert-butyl)-3- ((1S,3S,4S)-3-((tert-butyldiphenylsilyl) oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-amine (2.00 g, 4.00 mmol) in EA (20 mL) was added 2-(3-methylisoxazol-5-yl)acetic acid (0.60 g, 5.00 mmol) and DIEA (5.00 g, 40.00 mmol). Then T3P (20.00 g, 50% Wt, 30.00 mmol) was added dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at 25 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (120 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo resulted in a mixture of rac-N-(1-(tert- butyl)-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)-2- (3-methylisoxazol-5-yl)acetamide and rac-N-(1-(tert-butyl)-3-((1S,3S,4S)-3-((tert- butyldiphenylsilyl) oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5- yl)acetamide (1.20 g, 50 %) as a yellow solid. m/z (ES+) [M+H] + =603.40; HPLC tR = 1.482 min. rac-N-(1-(tert-butyl)-3-((1R,3S,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)-2-(3- methylisoxazol-5-yl)acetamide
Figure imgf000714_0001
[00413] Step 6. A round bottomed flask was charged with a mixture of rac-N-(1-(tert-butyl)-3- ((1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)-2-(3- methylisoxazol-5-yl)acetamide and rac-N-(1-(tert-butyl)-3-((1S,3S,4S)-3-((tert- butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5- yl)acetamide (1.15 g, 1.95 mmol), THF (12 mL) and a stirbar before being evacuated and purged with nitrogen three times. TBAF-3H2O (2.72 g, 9.77 mmol) was added and the solution was stirred for 1 hour at 50 °C. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with 17x30 mL of saturated brine, then the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 50% gradient in 20 min; detector, UV 254 nm, concentration in vacuo. The residue was purified by Prep-TLC (PE/EA; ratio:2/1) to afford rac-N-(1-(tert-butyl)-3-((1R,3S,4S)-3- fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide (0.32 g, 45.0 %) as a white solid. m/z (ES+) [M+H] + =365.25; HPLC tR = 0.836 min. rac-(1S,2S,4R)-4-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)-2- fluorocyclopentyl (4-nitrophenyl) carbonate
Figure imgf000714_0002
[00414] Step 7. To a mixture of rac-N-(1-(tert-butyl)-3-((1R,3S,4S)-3-fluoro-4- hydroxycyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide (300 mg, 0.82 mmol), Py (195 mg, 2.47 mmol) and DMAP (20 mg, 0.16 mmol) in DCM (3 mL) was added 4- nitrophenyl carbonochloridate (332 mg, 1.65 mmol) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h at 25 °C. The reaction mixture was diluted with H2O (15 mL), and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 70% gradient in 20 min; detector, UV 254 nm, Concentration in vacuo resulted in rac-(1S,2S,4R)-4-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5- yl)acetamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (4-nitrophenyl) carbonate (380 mg, 87.2 %) as a white solid. m/z (ES+) [M+H] + =530.45; HPLC tR = 0.958 min. rac-(1S,2S,4R)-4-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)-2- fluorocyclopentyl (1-methylcyclopropyl)carbamate
Figure imgf000715_0001
[00415] Step 8. A round bottomed flask was charged with rac-(1S,2S,4R)-4-(1-(tert-butyl)-5-(2- (3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (4-nitrophenyl) carbonate (370 mg, 0.70 mmol), 1-methylcyclopropan-1-amine hydrochloride (150 mg, 1.40 mmol), DIEA (452 mg, 3.49 mmol), and DMAP (8 mg, 0.07 mmol), THF (4 mL) and a stirbar before being evacuated and purged with nitrogen three times. The solution was stirred for 2 h at 25 °C. The reaction mixture was diluted with H2O (15 mL), and the aqueous phase was extracted with EA (30 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 60% gradient in 15 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1S,2S,4R)-4-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)-2- fluorocyclopentyl (1-methylcyclopropyl)carbamate (260 mg, 80.6 %) as a white solid. m/z (ES+) [M+H] + =462.45; HPLC tR = 0.858 min. rac-(1S,2S,4R)-2-fluoro-4-(5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3- yl)cyclopentyl (1-methylcyclopropyl)carbamate
Figure imgf000716_0001
[00416] Step 9. A round bottomed flask was charged with rac-(1S,2S,4R)-4-(1-(tert-butyl)-5-(2- (3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (1- methylcyclopropyl)carbamate (240 mg, 0.52 mmol), FA (3 mL) and a stirbar before being evacuated and purged with nitrogen three times, and the solution was stirred for 2 h at 80 °C. Concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 70% gradient in 15 min; detector, UV 254 nm. Concentration in vacuo resulted in rac-(1S,2S,4R)-2-fluoro-4-(5- (2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentyl (1- methylcyclopropyl)carbamate (120 mg, 56.9 %) as a white solid. m/z (ES+) [M+H] + =406.40.; HPLC tR = 0.742 min. rel-(1R,2R,4S)-2-fluoro-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5- yl)cyclopentyl (1-methylcyclopropyl)carbamate rel-(1S,2S,4R)-2-fluoro-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5- yl)cyclopentyl (1-methylcyclopropyl)carbamate
Figure imgf000716_0002
[00417] Step 10. rac-(1S,2S,4R)-2-fluoro-4-(5-(2-(3-methylisoxazol-5-yl)acetamido)-1H- pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl)carbamate (60 mg, 0.15 mmol)l was purified by chiral Pre-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.2% DEA)- -HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 18 min; Wave Length: 220/254 nm; RT1(min): 10.03; RT2(min): 14.82; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 1.4 mL; Number Of Runs: 4). Lyophilization yielded rel-(1R,2R,4S)-2-fluoro-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5- yl)cyclopentyl (1-methylcyclopropyl)carbamate (44.4 mg, 74 %) as a white amorphous solid. m/z (ES+) [M+H] + =406.15; HPLC tR = 0.862 min.1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.65 (s, 1H), 7.56 (s, 1H), 6.26 (d, 2H), 5.15 - 4.91 (m, 2H), 3.82 (s, 2H), 2.58 (dd, 1H), 2.20 (s, 4H), 1.97 (s, 1H), 1.87 (s, 1H), 1.24 (s, 4H), 0.61 (s, 2H), 0.48 (d, 2H). [00418] rac-(1S,2S,4R)-2-fluoro-4-(5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3- yl)cyclopentyl (1-methylcyclopropyl)carbamate (60 mg, 0.15 mmol)l was purified by chiral Pre- HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.2% DEA)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 18 min; Wave Length: 220/254 nm; RT1(min):10.03; RT2(min): 14.82; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 1.4 mL; Number Of Runs: 4). Lyophilization yielded rel- (1S,2S,4R)-2-fluoro-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate (44.5 mg, 74 %) as a white amorphous solid. m/z (ES+) [M+H] + =406.15; HPLC tR = 0.852 min.1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.64 (s, 1H), 7.56 (s, 1H), 6.26 (d, 2H), 5.21 - 4.91 (m, 2H), 3.82 (s, 2H), 2.63 - 2.55 (m, 1H), 2.20 (s, 4H), 1.96 (s, 1H), 1.57 (s, 1H), 1.24 (s, 4H), 0.61 (s, 2H), 0.48 (d, 2H). Example 19 (1S,2R,4R)-2-fluoro-4-(3-((8-(piperazin-1-yl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H- pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000718_0001
(1S,2R,4R)-4-(5-((8-bromoimidazo[1,2-c]pyrimidin-5-yl)amino)-1-(tert-butyl)-1H-pyrazol- 3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate [00419] Step 1. To a solution of (1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (500 mg, 1.43 mmol) in DMF (5 mL) was added NaH (285 mg, 60% Wt, 7.13 mmol) in portions at 0 °C. The mixture was stirred for 0.5 h under N2 atmosphere. A solution of 8-bromo-5-chloroimidazo[1,2-c]pyrimidine (431 mg, 1.85 mmol) in DMF was added under 0 °C and the mixture was allowed to warm to 25 °C and stirred for 1 h. The reaction was quenched with water and extracted with EA three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 10 min; detector, UV 254 nm to afford (1S,2R,4R)-4-(5-((8- bromoimidazo[1,2-c]pyrimidin-5-yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (320 mg, 586 μmol, 41.0 %) as a white solid. The product observed by LCMS (RT =0.797 min), m/z [M+H]+=546.15. (1S,2R,4R)-4-(1-(tert-butyl)-5-((8-(piperazin-1-yl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H- pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate [00420] Step 2. To a stirred solution of (1S,2R,4R)-4-(5-((8-bromoimidazo[1,2-c]pyrimidin-5- yl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1- ylcarbamate (150 mg, 274 μmol) in NMP (2.5 mL) was added piperazine (201 mg, 2.33 mmol). The reaction was stirred at 100 °C for 0.5 hour. The reaction was added with water and extracted with EA three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water (NH4HCO3), 100% gradient in 10 min; detector, UV 254 nm to afford (1S,2R,4R)-4-(1-(tert-butyl)-5-((8-(piperazin-1-yl)imidazo[1,2-c]pyrimidin-5-yl)amino)- 1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (50 mg, 91 μmol, 33 %) as a pink solid. The product observed by LCMS (RT =0.646 min), m/z [M+H]+=552.20. (1S,2R,4R)-2-fluoro-4-(3-((8-(piperazin-1-yl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H- pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate [00421] Step 3. A solution of (1S,2R,4R)-4-(1-(tert-butyl)-5-((8-(piperazin-1-yl)imidazo[1,2- c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1- ylcarbamate (50 mg, 90 μmol) in FA (2 mL) was stirred for 2 h at 100 degrees under N2 atmosphere. The residue was concentrated and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0%-100% gradient in 15 min; detector, UV 254 nm to afford crude product. The crude product was purified by Prep- HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: 20mm NaOH+10%ACN; Flow rate: 60 mL/min mL/min; Gradient: 12% B to 38% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.63). Lyophilization yielded (1S,2R,4R)-2-fluoro-4-(3- ((8-(piperazin-1-yl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (3 mg, 6 μmol, 8 %, 96.4% Purity) as a pink solid. The product observed by LCMS (RT =0.778 min), m/z [M+H]+=496.45.1H NMR (400 MHz, DMSO-d6) 12.15 (s, 1H), 9.68 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.50 (s, 1H), 7.08 (s, 1H), 6.52 (s, 1H), 5.06 (d, J = 55.0 Hz, 1H), 4.87 (s, 1H), 3.20 (d, J = 5.3 Hz, 5H), 2.87 (t, J = 4.8 Hz, 4H), 2.43-2.29 (m, 4H), 1.93 (s, 8H). Example 20 (1S,2R,4R)-2-fluoro-4-(3-((2-(piperazine-1-carbonyl)imidazo[1,2-c]pyrimidin-5-yl)amino)- 1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000720_0001
5-chloroimidazo[1,2-c]pyrimidine-2-carboxylic acid [00422] Step 1. A round bottom flask was charged with ethyl 5-chloroimidazo[1,2-c] pyrimidine- 2-carboxylate (380 mg, 1.68 mmol) and trimethyltinhydroxide (3.05 g, 16.8 mmol) in DCE (20 mL) and a stirbar, the solution was stirred for 1 h at 80 ºC under N2 atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with DCM 50ml. The filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 40% gradient in 10 min; detector, UV 254 nm. Concentration in vacuum resulted in 5-chloroimidazo[1,2-c] pyrimidine-2-carboxylic acid (170 mg, 0.71 mmol, 42 %, 83% Purity) as a white solid. Full conversion to product observed by LCMS (RT = 0.392 min), m/z [M+H]+= 198.05. tert-butyl 4-(5-chloroimidazo[1,2-c]pyrimidine-2-carbonyl)piperazine-1-carboxylate [00423] Step 2. To a stirred solution of 5-chloroimidazo[1,2-c] pyrimidine-2-carboxylic acid (240 mg, 1.21 mmol), DIEA (785 mg, 6.07 mmol) and tert-butyl piperazine-1-carboxylate (204 mg, 1.09 mmol) in EA (30 mL), T3P (2.32 g, 50% Wt in EA, 3.64 mmol) was added dropwise at 0 ℃ under N2 atmosphere. The resulting mixture was stirred for 1 h at 20℃ under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EA (100 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by Prep- TLC(EA:PE~1:3) to afford tert-butyl 4-(5-chloroimidazo[1,2-c] pyrimidine-2-carbonyl) piperazine-1-carboxylate (250 mg, 0.57 mmol, 47 %, 83% Purity) as a white solid. Full conversion to product observed by LCMS (RT = 0.689 min), m/z [M+H]+= 366.10. tert-butyl 4-(5-((3-((1R,3S,4R)-3-((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)-4- fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)amino)imidazo[1,2-c]pyrimidine-2- carbonyl)piperazine-1-carboxylate [00424] Step 3. To a stirred solution of (1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl bicycle [1.1.1] pentan-1-ylcarbamate (257 mg, 733 μmol) in DMF (10 mL) with 4A-MS at 0 degrees under N2 atmosphere, NaH (88 mg, 60% Wt, 2.20 mmol) was added and the resulting mixture was stirred for 10 min at 0 degrees under N2 atmosphere. Then tert-butyl 4-(5- chloroimidazo[1,2-c] pyrimidine-2-carbonyl) piperazine-1-carboxylate (268 mg, 733 μmol) was added in portions, the resulting mixture was stirred for 1 hour at 0 degrees under N2 atmosphere. Then The reaction was monitored by LCMS. The resulting mixture was quenched with 20 mL saturated of NH4Cl. The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x10mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-TLC (EA:PE~1:1) to afford tert-butyl 4-(5-((3-((1R,3S,4R)-3-((bicycle [1.1.1] pentan-1-ylcarbamoyl) oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl) amino) imidazo[1,2-c] pyrimidine-2- carbonyl) piperazine-1-carboxylate (120 mg, 177 μmol, 24.1 %) as a white solid. Full conversion to product observed by LCMS (RT = 1.104 min), m/z [M+H]+= 680.40. (1S,2R,4R)-2-fluoro-4-(3-((2-(piperazine-1-carbonyl)imidazo[1,2-c]pyrimidin-5-yl)amino)- 1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate [00425] Step 4. A solution of tert-butyl 4-(5-((3-((1R,3S,4R)-3-((bicycle [1.1.1] pentan-1- ylcarbamoyl) oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl) amino) imidazo[1,2-c] pyrimidine-2-carbonyl) piperazine-1-carboxylate (140 mg, 206 μmol) in HCOOH (140 mL) was stirred for 1.5 h at 100 degrees under N2 atmosphere. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3H2O), Mobile Phase B: 20mm NaOH+10%ACN; Flow rate: 60 mL/min mL/min; Gradient: 15% B to 38% B in 7 min; Wave Length: 220nm nm; RT1(min): 7.6; Number Of Runs: 4. This resulted in (1S,2R,4R)-2-fluoro-4-(3-((2-(piperazine-1-carbonyl) imidazo[1,2-c] pyrimidin-5-yl) amino)-1H-pyrazol-5-yl) cyclopentyl bicycle [1.1.1] pentan-1-ylcarbamate (9.4 mg, 17 μmol, 8.5 %, 97.1% Purity) as a white amorphous solid. Full conversion to product observed by LCMS (RT = 1.016 min), m/z [M+H]+= 524.25. 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.28 (s, 1H), 8.70 (s, 1H), 8.06 (s, 1H), 7.68 (s, 1H), 6.96 (s, 1H), 6.49 (s, 1H), 5.07 (d, J = 55.2 Hz, 1H), 4.85 (d, J = 22.5 Hz, 1H), 4.00 (s, 2H), 3.56 (s, 2H), 3.23 (d, J = 21.1 Hz, 2H), 2.74 (s, 4H), 2.37 (s, 3H), 1.93 (s, 8H). Example 21 (1S,2R,4R)-4-(3-((2-(azetidin-1-ylmethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol- 5-yl)-2-fluorocyclopentyl bicycle [1.1.1]pentan-1-ylcarbamate
Figure imgf000723_0001
ethyl 7-chloro-5-hydroxyimidazo[1,2-c] pyrimidine-2-carboxylate [00426] Step 1. A round bottomed flask was charged with 2,6-dichloropyrimidin-4-amine (20 g, 0.12 mol) and ethyl 3-bromo-2-oxopropanoate (60 g, 75% Wt, 0.23 mol) in AcOH (250 mL) and a stirbar, the solution was stirred for 3 hours at 120 °C. The mixture was concentrated in vacuum. The mixture was adjusted pH value to 6-7 with NaHCO3(aq), and the aqueous phase was extracted with DCM (200 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue product was purified by silica gel chromatography eluting with DCM/MeOH (ratio:20/1). Concentration in vacuum resulted in ethyl 7-chloro-5-hydroxyimidazo[1,2-c] pyrimidine-2-carboxylate (12.8 g, 32 mmol, 26 %, 60% Purity) as a yellow solid. Full conversion to product observed by LCMS (RT = 0.456 min), m/z [M+H]+=242.05. ethyl 5-hydroxyimidazo[1,2-c] pyrimidine-2-carboxylate [00427] Step 2. To a solution of ethyl 7-chloro-5-hydroxyimidazo[1,2-c] pyrimidine-2- carboxylate (10 g, 41 mmol) in MeOH (150 mL), Pd/C (10%, 1.2 g) was added under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 1 h under hydrogen atmosphere, filtered through a Celite pad and concentrated under reduced pressure to afford ethyl 5-hydroxyimidazo[1,2-c] pyrimidine-2-carboxylate (6.8 g, 26 mmol, 63 %, 80% Purity) as a white solid. Full conversion to product observed by LCMS (RT = 0.595 min), m/z [M+H]+=208.05. ethyl 5-chloroimidazo[1,2-c]pyrimidine-2-carboxylate [00428] Step 3. A round bottomed flask was charged with ethyl 5-hydroxyimidazo[1,2- c]pyrimidine-2-carboxylate (1 g, 5 mmol), POCl3 (20 mL) and a stirbar, and DIEA (10 mL) was added. Then the resulting solution was stirred for 16 hours at 100 °C under N2 atmosphere. The mixture was concentrated under reduced pressure. The reaction mixture was diluted with DCM (20 mL), the solution was added dropwise to the Sat. NaHCO3 and adjusted pH value to ~9, and the aqueous phase was extracted with DCM (3*50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 18 min; detector, UV 254 nm to afford ethyl 5-chloroimidazo[1,2-c]pyrimidine-2-carboxylate (300 mg, 1.33 mmol, 30 %) as a brown solid. Full conversion to product observed by LCMS (RT = 0.632 min), m/z [M+H]+= 226.00 ethyl 5-((3-((1R,3S,4R)-3-((bicyclo[1.1.1] pentan-1-ylcarbamoyl)oxy)-4-fluorocyclopentyl)- 1-(tert-butyl)-1H-pyrazol-5-yl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate [00429] Step 4. To a solution of ethyl 5-chloroimidazo[1,2-c] pyrimidine-2-carboxylate (110 mg, 488 μmol) and (1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (171 mg, 488 μmol) in Dioxane (3.5 mL), Potassium acetate (144 mg, 1.46 mmol), xantphos (113 mg, 195 μmol) and Pd2(dba)3 (89.3 mg, 97.5 μmol) were added in at 20 ºC under N2 atmosphere. The resulting mixture was stirred for 1 h at 80 ºC under N2 atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with 10 ml of H2O. The resulting mixture was extracted with DCM (3 x 10ml). The combined organic layers were washed with brine (1x10mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-TLC with the following conditions (EA/PE=1:1) to afford ethyl 5-((3-((1R,3S,4R)-3-((bicyclo[1.1.1] pentan-1-ylcarbamoyl)oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5- yl)amino)imidazo[1,2-c]pyrimidine-2-carboxylate (130 mg, 0.22 mmol, 44 %, 90% Purity) as a white solid. Full conversion to product observed by LCMS (RT = 1.156 min), m/z [M+H]+= 540.25. (1S,2R,4R)-4-(1-(tert-butyl)-5-((2-formylimidazo[1,2-c] pyrimidin-5-yl) amino)-1H-pyrazol- 3-yl)-2-fluorocyclopentyl bicycle [1.1.1] pentan-1-ylcarbamate [00430] Step 5. To a stirred solution of ethyl 5-((3-((1R,3S,4R)-3-((bicycle [1.1.1] pentan-1- ylcarbamoyl)oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)amino)imidazo[1,2-c] pyrimidine-2-carboxylate (200 mg, 371 μmol) in THF (10 mL), DIBAL-H (2.22 mL, 1M in hexanes, 2.22 mmol) was added into the reaction mixture at -60 ºC under N2 atmosphere. The resulting mixture was stirred for 0.25 h at -60 °C under N2 atmosphere. The reaction was monitored by LCMS. The resulting mixture was quenched with 20 ml of H2O. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (1x10mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-TLC (DCM/MeOH=15:1) to afford (1S,2R,4R)- 4-(1-(tert-butyl)-5-((2-formylimidazo[1,2-c] pyrimidin-5-yl) amino)-1H-pyrazol-3-yl)-2- fluorocyclopentyl bicycle [1.1.1] pentan-1-ylcarbamate (110 mg, 0.18 mmol, 50 %, 83% Purity) as a white solid. Full conversion to product observed by LCMS (RT = 0.760 min), m/z [M+H]+= 496.30. (1S,2R,4R)-4-(5-((2-(azetidin-1-ylmethyl) imidazo[1,2-c] pyrimidin-5-yl) amino)-1-(tert- butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicycle [1.1.1] pentan-1-ylcarbamate [00431] Step 6. A solution of (1S,2R,4R)-4-(1-(tert-butyl)-5-((2-formylimidazo[1,2-c] pyrimidin- 5-yl) amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicycle [1.1.1] pentan-1-ylcarbamate (100 mg, 202 μmol) in DCM (5 mL) was stirred at 0 ºC under N2 atmosphere. 1,3-Propylenimine (46.1 mg, 807 μmol) in DCM (1 mL) was added dropwise and the resulting mixture was stirred for additional 10 min at 0 ºC under N2 atmosphere. To the above mixture Sodium triacetoxyborohydride (85.5 mg, 404 μmol) was added, the resulting mixture was stirred for another 0.5 h at 0 ºC under N2 atmosphere, the reaction was monitored by LCMS. The resulting mixture was quenched with 20 ml saturated of NH4Cl. The resulting mixture was extracted with DCM (3 x 10mL). The combined organic layers were washed with brine (1x10mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-TLC with the following conditions (DCM/MeOH=10:1) to afford (1S,2R,4R)-4-(5-((2-(azetidin-1- ylmethyl) imidazo[1,2-c] pyrimidin-5-yl) amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl bicycle [1.1.1] pentan-1-ylcarbamate (50 mg, 86 μmol, 43 %, 92.8% Purity) as a white solid. Full conversion to product observed by LCMS (RT = 0.736 min), m/z [M+H]+= 537.40. (1S,2R,4R)-4-(3-((2-(azetidin-1-ylmethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol- 5-yl)-2-fluorocyclopentyl bicycle [1.1.1]pentan-1-ylcarbamate [00432] Step 7. A resealable reaction vial was charged with (1S,2R,4R)-4-(5-((2-(azetidin-1- ylmethyl) imidazo[1,2-c] pyrimidin-5-yl) amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl bicycle [1.1.1] pentan-1-ylcarbamate (10 mg, 19 μmol) in FA (0.5 mL), and a stirbar, and the mixture was stirred for 5 h at 100 °C under nitrogen atmosphere. This crude product 50 mg was ran in parallel. The reaction mixture was concentrated in vacuum, and the residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3H2O), Mobile Phase B: 20mm NaOH+10%ACN; Flow rate: 60 mL/min mL/min; Gradient: 20% B to 40% B in 7 min; Wave Length: 220nm nm; RT1(min): 7.55; Number Of Runs: 2. This resulted in (1S,2R,4R)-4-(3- ((2-(azetidin-1-ylmethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)-2- fluorocyclopentyl bicycle [1.1.1]pentan-1-ylcarbamate (2.0 mg, 4.1 μmol, 22 %, 98.4% Purity) as a white amorphous solid. Full conversion to product observed by LCMS (RT = 1.467 min), m/z [M+H]+= 481.20. 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.17 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H),7.62 (s, 1H), 6.86 (s, 1H), 6.66 (s, 1H), 5.25 – 4.95 (d, 1H), 5.00 (s, 1H), 3.59 (s, 2H), 3.23 (s, 3H), 2.42 (s, 2H), 2.00 (s, 13H). Example 22 (1R,2R,3R)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)cyclopentyl isopropylcarbamate (1S,2S,3S)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)cyclopentyl isopropylcarbamate
Figure imgf000727_0001
Figure imgf000728_0001
rac-ethyl (1R,2S)-2-hydroxycyclopentane-1-carboxylate [00433] Step 1. To a solution of ethyl 2-oxocyclopentane-1-carboxylate (40 g, 0.26 mol) in MeOH (1000 mL) was added NaBH4 (11 g, 0.28 mol) portion-wise under N2 at 0 °C. The reaction was stirred at 0 °C for 1 hour. TLC showed the reaction was completed. The mixture was quenched with acetone (40 mL), added sat. NH4Cl (600 mL) and extracted with MTBE(3*800 mL). The combined organic layers were washed with brine (2x300mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (300-400, PE/EA=20/1~10/1) to afford rac-ethyl (1R,2S)-2- hydroxycyclopentane-1-carboxylate (20.5 g, 130 mmol, 51 %) as yellow oil. m/z (ES+) [M+H] + = 159.05; HPLC tR = 0.667 min.1H NMR (400 MHz, Chloroform-d) 4.47 – 4.40 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.92 (s, 1H), 2.68 (ddd, J = 9.9, 8.7, 4.3 Hz, 1H), 2.09 – 1.86 (m, 3H), 1.85 – 1.72 (m, 2H), 1.71 – 1.56 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H). rac-ethyl (1R,2S)-2-(((methylthio)carbonothioyl)oxy)cyclopentane-1-carboxylate [00434] Step 2. To rac-ethyl (1R,2S)-2-hydroxycyclopentane-1-carboxylate (20.5 g, 130 mmol) in anhydrous DMSO was added DBU (11 g, 73 mmol) over ~5 minutes at room temperature under N2, the reaction was stirred at room temperature for 1 h. To above reaction was added CS2 (34 g, 0.45 mol), the reaction was stirred at room temperature for another 1.5 h. And then MeI (0.02 kg, 0.1 mol) was added into the above mixture over 20 mins. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with water (400 ml), and extracted with DCM (3*300 ml). The combined organic layers were washed with brine (3x100mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (330 g, PE/EA=0~10%, 30 min) to afford rac-ethyl (1R,2S)-2-(((methylthio)carbonothioyl)oxy)cyclopentane-1-carboxylate (8 g, 0.03 mol, 20 %) as yellow oil. m/z (ES+) [M+H] + = 249.05; HPLC tR = 0.892 min. 1H NMR (400 MHz, Chloroform-d) 6.15 (td, J = 5.3, 2.8 Hz, 1H), 4.24 – 4.04 (m, 2H), 3.04 (ddd, J = 9.9, 8.3, 5.7 Hz, 1H), 2.50 (s, 3H), 2.31 – 2.16 (m, 1H), 2.14 – 1.85 (m, 4H), 1.78 – 1.61 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H). ethyl cyclopent-2-ene-1-carboxylate [00435] Step 3. A round bottomed flask was charged with rac-ethyl (1R,2S)-2- (((methylthio)carbonothioyl)oxy) cyclopentane-1-carboxylate (26 g, 0.10 mol) and a stirbar, then the reaction mixture was stirred at 190 ºC for 3 hours to afford ethyl cyclopent-2-ene-1- carboxylate (14 g, 0.10 mol, 95 %) as yellow oil. m/z (ES+) [M+H] + = 141.10; HPLC tR = 0.892 min. rac-ethyl (2R,3S)-2,3-dihydroxycyclopentane-1-carboxylate [00436] Step 4. To a solution of ethyl cyclopent-2-ene-1-carboxylate (5 g,0.04 mol) in THF (40 mL) and Acetone (40 mL) were added a solution of NMO (8 g, 0.07 mol) and K2OsO4 (0.1 g, 0.4 mmol) in H2O (5 mL) at 0 °C under N2. The reaction was stirred at 25 °C for 5 hours. TLC showed the reaction was completed. The mixture was quenched with 10% Na2SO3 (10 mL) and sat. NH4Cl (10 mL), extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (flash, PE/EA~50% to 100% in 20 min) to afford rac-ethyl (2R,3S)-2,3-dihydroxycyclopentane-1-carboxylate (3.8 g, 22 mmol, 60 %) as yellow oil. m/z (ES+) [M+H] + = 175.15; HPLC tR = 0.385 min. rac-ethyl (3aR,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylate [00437] Step 5. To a solution of rac-ethyl (2R,3S)-2,3-dihydroxycyclopentane-1-carboxylate (3.8 g, 22 mmol) in Acetone (50 mL) was added 2,2-dimethoxypropane (23 g, 0.22 mol) stirred at 25 °C for 5 min. Then TsOH (0.41 g, 2.2 mmol) was added to the mixture, the mixture was stirred at 25 °C for 1 hour. The mixture was quenched with NaHCO3(10ml), and the aqueous phase was extracted with EA three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by silica gel chromatography (eluting with PE/EA~10/1). Concentration in vacuum resulted in rac-ethyl (3aR,6aS)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylate (3.2 g, 15 mmol, 68 %) as a yellow oil. m/z (ES+) [M+H] + = 215.05; HPLC tR = 0.742 min. rac-3-((3aR,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-3- oxopropanenitrile [00438] Step 6. To a solution of MeCN (6.1 g, 7.8 mL, 0.15 mol) in THF (40 mL) was added dropwise n-BuLi (18 mL, 45 mmol) at -78ºC under N2 atmosphere. The reaction mixture was stirred at -78 ºC for 1.5 hours. Then a solution of rac-ethyl (3aR,6aS)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxole-4-carboxylate (3.2 g, 15 mmol) in THF (8 mL) was added dropwise and the mixture was stirred for another 1 hour. The reaction was quenched with NH4Cl (10 mL), and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to afford rac-3-((3aR,6aS)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-3-oxopropanenitrile (2 g, 0.01 mol, 60 %) as a yellow oil. m/z (ES+) [M+H] + = 210.10; HPLC tR = 0.598 min. rac-1-(tert-butyl)-3-((3aR,4S,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4- yl)-1H-pyrazol-5-amine rac-1-(tert-butyl)-3-((3aS,4S,6aR)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4- yl)-1H-pyrazol-5-amine [00439] Step 7. A round bottomed flask was charged with rac-3-((3aR,6aS)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-3-oxopropanenitrile (3.2 g, 15 mmol), DIEA (9.9 g, 76 mmol) and t-BuNHNH2·HCl, (13 g, 0.11 mol) in iPOH (15 mL) and a stirbar, the solution was stirred for 16 hours at 80 °C. The resulting mixture was concentrated under vacuum, and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 60% gradient in 15 min; detector, UV 254 nm to afford rac-1-(tert-butyl)-3- ((3aR,4S,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazol-5-amine (2 g, 4 mmol, 30 %, 56% Purity) and rac-1-(tert-butyl)-3-((3aS,4S,6aR)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazol-5-amine (250 mg, 0.66 mmol, 4.3 %, 74% Purity) as off-white solid. Isomer 1:m/z (ES+) [M+H] + = 280.20; HPLC tR = 0.743 min. Isomer 2:m/z (ES+) [M+H] + = 280.20; HPLC tR = 0.777 min. [00440] Isomer 1:1H NMR (400 MHz, Chloroform-d) 5.60 (s, 1H), 4.65 (dt, J = 33.8, 5.4 Hz, 2H), 3.46 (s, 2H), 2.79 (dt, J = 12.9, 5.2 Hz, 1H), 1.96 - 1.74 (m, 4H), 1.61 (s, 9H), 1.50 (s, 3H), 1.30 (s, 3H). [00441] Isomer 2:1H NMR (400 MHz, Chloroform-d) 5.34 (d, J = 1.2 Hz, 1H), 4.85 - 4.78 (m, 1H), 4.70 (t, J = 5.4 Hz, 1H), 3.52 (s, 2H), 3.21 - 3.15 (m, 1H), 2.18 - 2.05 (m, 1H), 1.92 - 1.70 (m, 3H), 1.59 (s, 9H), 1.47 (s, 3H), 1.32 (s, 3H). rac-N-(1-(tert-butyl)-3-((3aR,4S,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol- 4-yl)-1H-pyrazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide [00442] Step 8. To a solution of rac-1-(tert-butyl)-3-((3aR,4S,6aS)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazol-5-amine (2 g, 7 mmol) and 3-(methoxymethyl)-1- methyl-1H-pyrazole-5-carboxylic acid (1 g, 8 mmol) in EA (45 mL) were added DIEA (5 g, 6 mL, 0.04 mol) and stirred at 0 °C. Then T3P (0.01 kg, 50% Wt, 0.02 mol) was added to the mixture, the mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with water, and the aqueous phase was extracted with EA three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 15 min; detector, UV 254 nm to obtain rac-N-(1- (tert-butyl)-3-((3aR,4S,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H- pyrazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (1.6 g, 3.2 mmol, 40 %, 86% Purity) as an off-white solid. m/z (ES+) [M+H] + = 432.20; HPLC tR = 0.763 min. rac-N-(1-(tert-butyl)-3-((1S,2R,3S)-2,3-dihydroxycyclopentyl)-1H-pyrazol-5-yl)-3- (methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide [00443] Step 9. A round bottomed flask was charged with rac-N-(1-(tert-butyl)-3-((3aR,4S,6aS)- 2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazol-5-yl)-3-(methoxymethyl)- 1-methyl-1H-pyrazole-5-carboxamide (1.6 g, 3.7 mmol) in aq. HCl (15 mL, 1 molar, 15 mmol) and a stirbar, the solution was stirred for 4 hours at 25 °C. The reaction mixture was concentrated in vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 40% gradient in 10 min; detector, UV 254 nm to obtain rac-N-(1-(tert-butyl)-3-((1S,2R,3S)-2,3-dihydroxycyclopentyl)- 1H-pyrazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (1.2 g, 3.0 mmol, 81 %, 98.3% Purity) as a white solid. m/z (ES+) [M+H] + = 392.10; HPLC tR = 0.642 min. rac-N-(3-((1S,2R,3S)-3-(benzyloxy)-2-hydroxycyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)- 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide [00444] Step 10. To a solution of rac-N-(1-(tert-butyl)-3-((1S,2R,3S)-2,3-dihydroxycyclopentyl)- 1H-pyrazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (900 mg, 2.30 mmol) in Toluene (10 mL) was added Bu2SnO (630 mg, 2.53 mmol) at 25 °C, the mixture was stirred at 120 °C for 3 hours. Then CsF (384 mg, 2.53 mmol) and Benzyl bromide (433 mg, 2.53 mmol) were added to the mixture, the mixture was stirred at 120 °C for 1 hour. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 10 min; detector, UV 254 nm to afford rac- N-(3-((1S,2R,3S)-3-(benzyloxy)-2-hydroxycyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)-3- (methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (600 mg, 1.01 mmol, 43.8 %, 80.9% Purity) as a white solid. m/z (ES+) [M+H] + = 482.50; HPLC tR = 1.093 min. rac-N-(3-((1S,2S,3S)-3-(benzyloxy)-2-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)-3- (methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide [00445] Step 11. To a solution of rac-N-(3-((1S,2R,3S)-3-(benzyloxy)-2-hydroxycyclopentyl)-1- (tert-butyl)-1H-pyrazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (600 mg, 1.25 mmol) in DCM (48 mL), BAST (2.76 g, 12.5 mmol) was added at 0 ºC. Then the mixture was stirred at 0 °C for 1 hour. the reaction was quenched with sat. NaHCO3(aq), and then the mixture was extracted with DCM (3 x20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 10 min; detector, UV 254 nm. to afford rac-N-(3- ((1S,2S,3S)-3-(benzyloxy)-2-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)-3- (methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (200 mg, 100 μmol, 8.03 %, 24.2% Purity) as a yellow oil. m/z (ES+) [M+H] + = 484.30; HPLC tR = 1.243 min. rac-N-(1-(tert-butyl)-3-((1S,2S,3S)-2-fluoro-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)-3- (methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide [00446] Step 12. To a solution of rac-N-(3-((1S,2S,3S)-3-(benzyloxy)-2-fluorocyclopentyl)-1- (tert-butyl)-1H-pyrazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (200 mg, 414 μmol) and NH3·H2O(0.5 mL) in MeOH (5 mL), Pd/C (440 mg) was added under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 16 hours under hydrogen atmosphere, filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 60% gradient in 10 min; detector, UV 254 nm to afford rac-N-(1-(tert-butyl)-3-((1S,2S,3S)-2-fluoro-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)-3- (methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (40 mg, 0.10 mmol, 24 %, 98.8% Purity) as a white solid. m/z (ES+) [M+H] + = 394.20; HPLC tR = 0.621 min. rac-(1S,2S,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (4-nitrophenyl) carbonate [00447] Step 13. To a stirred solution of rac-N-(1-(tert-butyl)-3-((1S,2S,3S)-2-fluoro-3- hydroxycyclopentyl)-1H-pyrazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5- carboxamide (35 mg, 89 μmol), Py (21 mg, 0.27 mmol) and DMAP (2.2 mg, 18 μmol) in DCM (3 mL) was added 4-nitrophenyl carbonochloridate (22 mg, 0.11 mmol) under 0 °C. The reaction was stirred at 25 °C for 3 hours. The reaction mixture was diluted with water, and the aqueous phase was extracted with DCM three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to obtain rac-(1S,2S,3S)-3-(1-(tert-butyl)- 5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2- fluorocyclopentyl (4-nitrophenyl) carbonate (45 mg, 49 μmol, 55 %, 61% Purity) as a yellow oil. m/z (ES+) [M+H] + = 559.20; HPLC tR = 1.218 min. rac-(1S,2S,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl isopropylcarbamate [00448] Step 14. To a stirred solution of rac-(1S,2S,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)- 1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (4-nitrophenyl) carbonate (40 mg, 72 μmol) in THF (2 mL) were added propan-2-amine (13 mg, 0.21 mmol) and DIEA (46 mg, 0.36 mmol). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 70% gradient in 10 min; detector, UV 220 nm. Concentration in vacuum resulted in rac-(1S,2S,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)- 1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl isopropylcarbamate (25 mg, 46 μmol, 65 %, 88.8% Purity) as an off-white solid. m/z (ES+) [M+H] + =479.25; HPLC tR = 0.741 min. rac-(1S,2S,3S)-2-fluoro-3-(5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)- 1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [00449] Step 15. A round bottomed flask was charged with rac-(1S,2S,3S)-3-(1-(tert-butyl)-5-(3- (methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl isopropylcarbamate (20 mg, 42 μmol) in FA (2 mL) and a stirbar, the solution was stirred for 1 hour at 80 °C. The resulting mixture was concentrated under vacuum to obtain rac-(1S,2S,3S)-2- fluoro-3-(5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3- yl)cyclopentyl isopropylcarbamate (15 mg, 34 μmol, 80 %, 94.7% Purity) as a white solid. m/z (ES+) [M+H] + = 423.30; HPLC tR = 0.688 min. (1R,2R,3R)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)cyclopentyl isopropylcarbamate (1S,2S,3S)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H- pyrazol-5-yl)cyclopentyl isopropylcarbamate [00450] Step 16. The resulting crude material was purified by chiral Pre-HPLC (Column: CHIRALPAK IC, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH), Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 12 min; Wave Length: 220/254 nm; RT1(min): 4.55; RT2(min): 8.59; Sample Solvent: EtOH: DCM=1: 1; Sample concentration: mg/mL; Injection Volume: 1.7 mL; Number Of Runs: 1). Lyophilization yielded rel-(1R,2R,3R)-2-fluoro-3-(3-(3- (methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (6.2 mg, 13 μmol, 31 %, 90.0% Purity) as a white solid and rel-(1S,2S,3S)-2- fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-5- yl)cyclopentyl isopropylcarbamate (5.1 mg, 12 μmol, 28 %) as a white solid. [00451] Rel-(1R,2R,3R)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate: m/z (ES+) [M+H] + = 423.20; HPLC tR = 1.287 min.1H NMR (400 MHz, DMSO-d6) 12.44 (s, 1H), 10.79 (s, 1H), 7.30 - 7.04 (m, 2H), 6.54 (s, 1H), 5.09 - 4.84 (m, 2H), 4.34 (s, 2H), 4.05 (s, 3H), 3.59 (q, J = 6.8 Hz, 1H), 3.44 (s, 1H), 3.27 (s, 3H), 2.17 (s, 2H), 1.88 (d, J = 11.2 Hz, 1H), 1.68 (s, 1H), 1.05 (d, J = 6.6 Hz, 6H). [00452] Rel-(1S,2S,3S)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5- carboxamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate: m/z (ES+) [M+H] + = 423.20; HPLC tR = 1.270 min.1H NMR (400 MHz, DMSO-d6) 12.44 (s, 1H), 10.79 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.03 (dd, J = 15.8, 7.3 Hz, 2H), 4.87 (s, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 3.59 (dq, J = 13.4, 6.6 Hz, 1H), 3.27 (s, 3H), 2.19 (d, J = 16.9 Hz, 2H), 1.95 - 1.80 (m, 1H), 1.72 (d, J = 29.6 Hz, 1H), 1.05 (d, J = 6.5 Hz, 6H). [00453] Additional compounds prepared according to the methods of Example 22 are depicted in Table 9 below. Table 9. Additional Exemplary Compounds
Figure imgf000736_0001
Example 23 (1S,2S,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (Synthetic Intermediate)
Figure imgf000737_0001
benzyl (3-((1R,3r,5S)-6-oxabicyclo[3.1.0]hexan-3-yl)-1-(tert-butyl)-1H-pyrazol-5- yl)carbamate [00454] Step 1. To a solution of benzyl (1-(tert-butyl)-3-(cyclopent-3-en-1-yl)-1H-pyrazol-5- yl)carbamate (70.0 g, 206 mmol, 1.00 eq) in MeOH (1.40 L) was added NaHCO3 (52.0 g, 619 mmol, 24.1 mL, 3.00 eq) at 25 °C. Then m-CPBA (89.0 g, 412 mmol, 80% purity, 2.00 eq) was added to the mixture at 0 °C in portions. The mixture was stirred at 25 °C for 12 hrs. HPLC showed starting material (Rt = 3.177 mins) remained and one peak (Rt = 2.631 mins) was detected. The reaction mixture was poured into H2O (2.00 L) and extracted with ethyl acetate (1.00 L * 3). The organic phase was washed with saturated NaHCO3 aqueous solution (1.50 L * 3), saturated sodium sulfite solution (2.00 L), brine (2.00 L), dried with anhydrous Na2SO4. The organic phase was concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 5: 1 to 3: 1, Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.47, I2). The fraction was concentrated in vacuum to give a residue (50.0 g). The residue was further separated by SFC (neutral condition: column: DAICEL CHIRALPAK AD (250mm*50mm, 10 um); mobile phase: [NEU TRI-IPA]; B%: 35%-35%, 4.0 mins). The eluent was concentrated under vacuum to give benzyl (3-((1R,3r,5S)-6-oxabicyclo[3.1.0]hexan-3-yl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (11.8 g, 31.0 mmol, 93.2% purity, 15.0% yield) as yellow oil. HPLC: product: Rt = 2.631 mins, 6.89% purity under 220 nm. LCMS: product: Rt = 0.593 min, m/z = 356.3 [M+H]+ HPLC: product: Rt = 2.637 mins, 93.2% purity under 220 nm.1H NMR: (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.38 - 7.33 (m, 5H), 5.85 (s, 1H), 5.11 (s, 2H), 3.49 (s, 2H), 3.23 - 3.21 (m, 1H), 2.13 - 2.02 (m, 4H), 1.46 (s, 9H). benzyl (1-(tert-butyl)-3-((1R,3S,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5- yl)carbamate [00455] Step 2. To a solution of (S, S, S, S) -dimeric (salen) Co (II) complex (1.07 g, 844 umol, 0.05 eq) in MTBE (60.0 mL) was added DBN (167 mg, 1.35 mmol, 161.3 uL, 0.08 eq) at 25 °C, benzyl (3-((1R,3r,5S)-6-oxabicyclo[3.1.0]hexan-3-yl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (6.00 g, 16.9 mmol, 1.00 eq), benzoyl fluoride (4.19 g, 33.8 mmol, 2.00 eq) and 1,1,1,3,3,3- hexafluoropropan-2-ol (11.4 g, 67.5 mmol, 4.00 eq) was added, followed by 2-hydroperoxy-2- methyl-propane (5 M, 338 uL, 0.10 eq), the mixture was stirred at 25 °C for 12 hrs. TLC (Petroleum ether: Ethyl acetate = 1: 1) showed benzyl (3-((1R,3r,5S)-6-oxabicyclo[3.1.0]hexan-3- yl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (Rf = 0.60) was consumed and a new main spot (Rf = 0.30) was detected. The mixture was poured into saturated NaHCO3 aqueous solution (100 mL) and extracted with ethyl acetate (100 mL * 2). The combined organic phase was washed with brine (100 mL * 2), dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 10: 1 to 5: 1, Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.30) to give benzyl (1-(tert-butyl)-3-((1R,3S,4S)-3- fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (5.30 g, 14.1 mmol, 83.6% yield) as yellow oil. (1S,2S,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl 1H-imidazole-1-carboxylate [00456] Step 3. To a solution of benzyl (1-(tert-butyl)-3-((1R,3S,4S)-3-fluoro-4- hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (2.20 g, 5.86 mmol, 1.00 eq) in THF (44.0 mL) was added CDI (3.80 g, 23.44 mmol, 4.00 eq). The mixture was stirred at 25 °C for 2 hrs. LCMS showed benzyl (1-(tert-butyl)-3-((1R,3S,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5- yl)carbamate was consumed and desired MS (Rt = 0.531 min) was detected. The reaction mixture was poured into H2O (50.0 mL), the aqueous phase was extracted with ethyl acetate (40.0 mL * 2). The combined organic phase was washed with brine (60.0 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give (1S,2S,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1- (tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl 1H-imidazole-1-carboxylate (3.50 g, crude) as brown oil. LCMS: product: Rt = 0.531 min, m/z = 470.2 [M+H]+. benzyl (3-((1R,3S,4S)-3-((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)-4-fluorocyclopentyl)-1- (tert-butyl)-1H-pyrazol-5-yl)carbamate [00457] Step 4. To a solution of (1S,2S,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)- 1H-pyrazol-3-yl)-2-fluorocyclopentyl 1H-imidazole-1-carboxylate (3.5 g, 7.45 mmol, 1.00 eq) and bicyclo[1.1.1]pentan-1-amine hydrochloride (8.92 g, 74.6 mmol, 10.0 eq, HCl) in 2-Me-THF (35.0 mL) was added TEA (11.3 g, 112 mmol, 15.6 mL, 15.0 eq) at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 12 hrs. LCMS showed starting material was consumed completely and desired mass (Rt = 0.601 min) was detected. The reaction mixture was poured into H2O (50.0 mL), the aqueous phase was extracted with ethyl acetate (40.0 mL * 2). The combined organic phase was washed with brine (60.0 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give a crude product. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 5: 1 to 3: 1, Petroleum ether: Ethyl acetate = 2: 1, Rf = 0.40). The fraction was concentrated under vacuum to give benzyl (3-((1R,3S,4S)-3- ((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5- yl)carbamate (1.50 g, 3.10 mmol, 52.8% yield over two steps) as a white solid. LCMS: product: Rt = 0.601 min, m/z = 485.3 (M+H)+ 1H NMR: (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.96 (s, 1H), 7.53 - 7.24 (m, 5H), 5.98 (s, 1H), 5.11 (s, 2H), 5.09 - 4.88 (m, 2H), 3.29 - 3.16 (m, 1H), 2.39 - 2.28 (m, 1H), 2.25 - 2.10 (m, 1H), 1.99 (s, 7H), 1.71 - 1.55 (m, 1H), 1.48 (s, 9H). (1S,2S,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate [00458] Step 5. To a solution of benzyl (3-((1R,3S,4S)-3-((bicyclo[1.1.1]pentan-1- ylcarbamoyl)oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (1.30 g, 2.68 mmol, 1.00 eq) in THF (13.0 mL) and EtOAc (13.0 mL) added Pd/C (130 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (50 psi) at 25 °C for 3 hrs. TLC (Petroleum ether: Ethyl acetate= 2: 1, I2) indicated starting material (Rf = 0.45) was consumed completely and one new spot (Rf = 0.30) was formed. The mixture was filtered and concentrated under reduced pressure to give a product. The crude product was purified by prep-HPLC (column: Waters Xbridge C18150*50mm * 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 32%-62%, 10 mins), the eluent was concentrated in vacuum to remove ACN. The residual aqueous solution was lyophilized to give (1S,2S,4R)-4- (5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1- ylcarbamate (701.82 mg, 1.99 mmol, 74.6% yield, 99.3% purity) as a yellow solid. LCMS: product: Rt = 0.432 min, m/z = 351.2 (M+H)+; HPLC: product: Rt = 1.739 mins, 99.3% purity under 220 nm.1H NMR: (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 5.23 (s, 1H), 5.04 - 4.92 (m, 2H), 4.75 (s, 2H), 3.10 - 3.08 (m, 1H), 2.36 - 2.34 (m, 2H), 2.10 - 2.07 (m, 1H), 1.91 (s, 7H), 1.57 - 1.56 (m, 1H), 1.48 (s, 9H). Example 24 (1R,2R,4S)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (Synthetic Intermediate)
Figure imgf000740_0001
Figure imgf000741_0001
benzyl (1-(tert-butyl)-3-((1S,3R,4R)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5- yl)carbamate [00459] Step 1. To a solution of (R, R, R, R) -dimeric (salen) Co (II) complex (801 mg, 633 μmol, 0.050 eq) in MTBE (80.0 mL) was added DBN (126 mg, 1.01 mmol, 121 μL, 0.08 eq) at 25 °C, benzyl (4-((1R,3r,5S)-6-oxabicyclo[3.1.0]hexan-3-yl)-1-(tert-butyl)-1H-pyrrol-2-yl)carbamate (4.50 g, 12.7 mmol, 1.00 eq), benzoyl fluoride (3.14 g, 25.3 mmol, 2.00 eq) and 1, 1, 1, 3, 3, 3- hexafluoropropan-2-ol (8.51 g, 50.6 mmol, 4.00 eq) was added, followed by 2-hydroperoxy-2- methyl-propane (5 M, 253 μL, 0.100 eq) at 25 °C, the mixture was stirred at 25 °C for 12 hrs. LCMS showed starting material was consumed and the desired MS (Rt = 0.706 min) was detected. The mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 5: 1 to 4: 1, Petroleum ether: Ethyl acetate = 2: 1, Rf = 0.50). benzyl (1-(tert-butyl)-3-((1S,3R,4R)-3-fluoro-4-hydroxycyclopentyl)-1H- pyrazol-5-yl)carbamate (3.57 g, 8.70 mmol, 68.7% yield, 91.5% purity) was obtained as yellow oil. LCMS: product: Rt = 0.706 min, m/z = 376.2 (M+H)+ HPLC:, product: Rt = 2.619 mins, 91.5% purity under 220 nm.1H NMR: (400 MHz, DMSO-d6) δ 9.13 - 9.06 (m, 1H), 7.39 - 7.34 (m, 5H), 5.96 (s, 1H), 5.18 (d, J = 4.8 Hz, 1H), 5.12 (s, 2H), 4.92 - 4.77 (m, 1H ), 4.16 - 4.09 (m, 1H ), 3.18 - 3.11 (m, 1H), 2.36 - 2.34 (m, 1H), 2.09 - 1.99 (m, 2H ), 1.57 - 1.51 (m, 1H), 1.48 (s, 9H). (1R,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl 1H-imidazole-1-carboxylate [00460] Step 2. To a solution of benzyl (1-(tert-butyl)-3-((1S,3R,4R)-3-fluoro-4- hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (1.40 g, 3.54 mmol, 94.9% purity, 1.00 eq) in THF (26.0 mL) was added CDI (2.30 g, 14.2 mmol, 4.00 eq) at 25 °C, the mixture was stirred at 25 °C for 4 hrs. LCMS showed starting material was consumed and the desired MS (Rt = 0.717 min) was detected. The reaction mixture was poured into water (20.0 mL) and extracted with ethyl acetate (15.0 mL * 2), the organic phase was washed with brine (20.0 mL) and dried over Na2SO4 and concentrated under vacuum. (1R,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)- 1H-pyrazol-3-yl)-2-fluorocyclopentyl 1H-imidazole-1-carboxylate (1.66 g, crude) was obtained as yellow oil. The crude product was used to next step without purification. LCMS: product: Rt = 0.717 min, m/z = 470.2 (M+H)+ benzyl (3-((1S,3R,4R)-3-((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)-4-fluorocyclopentyl)-1- (tert-butyl)-1H-pyrazol-5-yl)carbamate [00461] Step 3. To a solution of (1R,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)- 1H-pyrazol-3-yl)-2-fluorocyclopentyl 1H-imidazole-1-carboxylate (1.66 g, 3.54 mmol, crude purity, 1.00 eq) in 2-Me-THF (16.0 mL) was added TEA (5.37 g, 53.0 mmol, 7.38 mL, 15.0 eq) and bicyclo[1.1.1]pentan-1-amine hydrochloride (4.23 g, 35.4 mmol, 10.0 eq, HCl) at 25 °C, the mixture was heated to 60 °C and stirred at 60 °C for 12 hrs. LCMS showed starting material was consumed and the desired MS (Rt = 0.825 min) was detected. The mixture was cooled to 25 °C, diluted with water (10.0 mL), extracted with ethyl acetate (10.0 mL * 2), combined organic layers were washed with brine (10.0 mL), dried with Na2SO4, filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 22 to 100: 25, Petroleum ether: Ethyl acetate = 2: 1, Rf = 0.38). benzyl (3-((1S,3R,4R)-3- ((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5- yl)carbamate (1.25 g, 2.51 mmol, 70.9% yield, 97.2% purity) was obtained as a white solid. LCMS: product: Rt = 0.825 min, m/z = 485.3 (M+H)+. HPLC: product: Rt = 3.326 mins, 97.2% purity under 220 nm.1H NMR: (400 MHz, DMSO-d6) δ 9.14 - 9.08 (m, 1H), 7.96 (br d, J = 1.6 Hz, 1H ), 7.37 - 7.33 (m, 5H), 5.98 (s, 1H), 5.11 (s, 2H), 5.08 - 4.95 (m, 2H ),3.25 - 3.20 (m, 1H), 2.36 - 2.33 (m, 1H), 2.24 - 2.15 (m, 1H ), 2.00 - 1.82 (m, 7H ), 1.64 - 1.60 (m, 1H), 1.47 (s, 9H). (1R,2R,4S)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate [00462] Step 4. To a solution of benzyl (3-((1S,3R,4R)-3-((bicyclo[1.1.1]pentan-1- ylcarbamoyl)oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (1.35 g, 2.79 mmol, 1.00 eq) in Ethyl acetate (13.0 mL), THF (13.0 mL) was added Pd/C (250 mg, 10% purity, 1.00 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi) at 25 °C for 3 hrs. LCMS showed starting material was consumed and the desired MS (Rt = 0.883 min) was detected. The reaction mixture was filtered directly and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50 mm* 10um;mobile phase: [water (NH4HCO3) -ACN]; B%: 32%-62%, 10 min), the eluent was concentrated to remove most ACN and lyophilized. (1R,2R,4S)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (736 mg, 2.09 mmol, 75.4% yield, 99.5% purity) was obtained as a yellow solid.LCMS: product: Rt = 0.883 min, m/z = 351.3 (M+H)+. HPLC: product: Rt = 1.698 mins, 99.5% purity under 220 nm.1H NMR: (400 MHz, DMSO-d6) δ 7.94 (br s, 1H), 5.23 (s, 1H ), 5.04 - 4.92 (m, 2H), 4.76 (s, 2H), 3.09 (br d; J = 7.20 Hz, 1H), 2.45 - 2.42 (m, 1H ), 2.36 - 2.33 (m, 1H), 2.10 - 2.07 (m, 1H), 1.91 (br s, 7H ), 1.64 - 1.56 (m, 1H), 1.48 (s, 9H). Example 25 (1S,2S,4R)-2-fluoro-4-(5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000743_0001
(1S,2S,4R)-4-(1-(tert-butyl)-5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate [00463] Step 1. To a solution of (1S,2S,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (80.0 mg, 228 μmol, 1.00 eq) in EtOAc (0.80 mL) was added 1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxylic acid (56.3 mg, 251 μmol, 1.10 eq) and DIEA (73.8 mg, 571 μmol, 99.4 μL, 2.50 eq) at 25 °C. Then T3P (602 mg, 946 μmol, 563 μL, 50.0% purity, 4.15 eq) was drop wise added at 0 °C. The mixture was heated to 70 °C and stirred at 70 °C for 12 hrs. TLC (Petroleum ether: Ethyl acetate = 1: 1) showed starting material (Rf = 0.40) was consumed and a new main spot (Rf = 0.60) was formed. The reaction mixture was cooled to 25 °C, then poured into ice water (10.0 mL), extracted with ethyl acetate (10.0 mL * 2). The combined organic layers were washed with sat.NaHCO3 aqueous solution (10.0 mL), brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. (1S,2S,4R)-4-(1-(tert-butyl)-5-(1-methyl-3- ((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (100 mg, 166 μmol, crude) was obtained as yellow oil. LCMS: product: RT = 0.591 min, m/z = 557.3 (M+H)+. (1S,2S,4R)-2-fluoro-4-(5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate [00464] Step 2. To a solution of (1S,2S,4R)-4-(1-(tert-butyl)-5-(1-methyl-3- ((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (80.0 mg, 144 μmol, 1.00 eq) was dissolved in Formic acid (0.80 mL) at 25 °C. The mixture was heated to 65 °C and stirred at 65 °C for 10 hrs. LCMS showed starting material was consumed and desired MS (RT = 0.525 min) was detected. The reaction mixture was poured into H2O (10.0 mL), the aqueous phase was extracted with ethyl acetate (10.0 mL * 2). The combined organic phase was washed with saturated NaHCO3 aqueous solution (10 mL * 2) and brine (10 mL * 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water(FA)-ACN]; gradient:42%-72% B over 10 min), the eluent was concentrated in vacuum to remove ACN. The residual aqueous solution was lyophilized to give a product. (1S,2S,4R)-2-fluoro-4-(5-(1-methyl- 3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (13.55 mg, 26.2 μmol, 18.2% yield, 96.7% purity) was obtained as a white solid. LCMS: product: RT = 0.525 min, m/z = 501.2 (M+H)+ HPLC: product: RT = 2.913 mins, 96.7% purity under 220 nm.1H NMR: (400 MHz, DMSO-d6) δ 12.3 (s, 1H) 10.9 (s, 1H) 8.05 - 7.92 (m, 1H) 7.28 (s, 1H) 6.53 - 6.38 (m, 1H) 5.17 - 4.96 (m, 4H) 4.09 (s, 3H) 2.70 - 2.53 (m, 2H) 2.37 (s, 1H) 2.34 - 2.18 (m, 1H) 1.92 (s, 7H) 1.71 - 1.56 (m, 1H) Example 26 (1R,2R,4S)-2-fluoro-4-(5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate
Figure imgf000745_0001
(1R,2R,4S)-4-(1-(tert-butyl)-5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate [00465] Step 1. To a solution of (1R,2R,4S)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2- fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (80.0 mg, 228.29 μmol, 1.00 eq) in EtOAc (1.00 mL) was added 1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxylic acid (56.29 mg, 251.12 μmol, 1.10 eq), DIEA (73.76 mg, 570.73 μmol, 99.41 μL, 2.50 eq) .Then T3P (830 mg, 1.30 mmol, 776.43 μL, 50% purity, 5.71 eq) was added at 0 °C. The mixture was heated to 67 °C and stirred at 67 °C for 12 hrs. TLC (Petroleum ether: Ethyl acetate = 2: 1) indicated starting material (Rf = 0.40) was consumed and a main new spot (Rf = 0.60) was formed. The reaction mixture was cooled to 25 °C, then poured into ice water (5.00 mL), extracted with ethyl acetate(5.00 mL * 2). The combined organic layers were washed with sat.NaHCO3 aqueous solution (5.00 mL * 4), brine (5.00 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The reaction was used to next step without purification. (1R,2R,4S)-4-(1-(tert-butyl)-5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (90.0 mg, 121.28 μmol, 53.13% yield, 75% purity) was obtained as a yellow solid. LCMS: product: RT = 0.586 min, m/z = 557.4 (M+H)+. (1R,2R,4S)-2-fluoro-4-(5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- carboxamido)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate [00466] Step 2. A mixture of (1R,2R,4S)-4-(1-(tert-butyl)-5-(1-methyl-3- ((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (80.0 mg, 143.74 μmol, 1.00 eq) in Formic acid (1.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 65 °C for 10 hrs under N2 atmosphere. LCMS showed 4.9% of starting material was remained and the desired MS (RT = 0.531 min) was detected. The reaction mixture was cooled to 25 °C, then poured into water (10.0 mL), extracted with ethyl acetate (10.0 mL * 2). The combined organic layers were washed with sat.NaHCO3 aqueous solution (10.0 mL * 4), brine (10.0 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed- phase HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)- ACN];gradient:46%-73% B over 9 min, adjusted pH to 7-8 with sat.NaHCO3 solution, concentrated to remove most of ACN, extracted with ethyl acetate (10.0 mL * 2). The combined organic layers were washed with brine (10.0 mL * 2), dried over Na2SO4, filtered, concentrated and lyophilized to give product. (1R,2R,4S)-2-fluoro-4-(5-(1-methyl-3- ((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (18.0 mg, 35.39 μmol, 24.6% yield, 98.4% purity) was obtained as a white solid. LCMS: product: RT = 0.531 min, m/z = 501.2 (M+H)+; LCMS: product: RT = 0.587 min, m/z = 501.2 (M+H)+. HPLC: product: RT = 2.768 mins, 98.4% purity under 220 nm. 1H NMR: (400 MHz, DMSO) δ 12.32 (br d, J = 1.6 Hz, 1H), 10.87 (s, 1H), 7.99 -7.98 (m, 1H), 7.28 (s, 1H), 6.47 (br s, 1H), 5.10 - 4.98 (m, 4H), 4.09 (s, 3H), 2.65 - 2.58 (m, 2H), 2.38 - 2.35 (m, 2H), 1.95 - 1.88 (m, 7H), 1.67 - 1.60 (m, 1H). Example 27 Methyl (2R,3R,4R)-3,4-dihydroxytetrahydrofuran-2-carboxylate (Synthetic Intermediate)
Figure imgf000747_0001
(3aR,7S,7aS)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6,7-diol [00467] Step 1. To a solution of (3S,4R,5R)-tetrahydro-2H-pyran-2,3,4,5-tetraol (150 g, 999 mmol, 1.00 eq) and 2,2-dimethoxypropane (312 g, 3.00 mol, 367 mL, 3.00 eq) in DMF (150 mL) was added TsOH•H2O (1.90 g, 9.99 mmol, 0.01 eq) at 20 °C under N2. The mixture was stirred at 18 - 20 °C for 12 hrs. Then the mixture was heated to 32 °C and stirred at 32 °C for 5 hrs. TLC (Petroleum ether/Ethyl acetate = 0/1, PMA) showed starting material (Rf = 0.15) was consumed and several spots (Rf = 0.34, 0.44, 0.72, 0.90) were formed. The reaction mixture was concentrated under vacuum to remove DMF and 2,2-dimethoxypropane. The mixture was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate = from 50/1 to 0/1, Petroleum ether/Ethyl acetate = 0/1, Rf = 0.34 & 0.44) to give (3aR,7S,7aS)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5- c]pyran-6,7-diol (72.0 g, 379 mmol) as colorless oil. 1H NMR: (400 MHz, DMSO-d6). δ 6.59 - 5.79 (m, 1H), 5.38 - 4.87 (m, 1H), 4.85 - 4.42 (m, 1H), 4.21 - 4.09 (m, 1H), 4.02 - 3.87 (m, 2H), 3.69 - 3.64 (m, 1H), 3.55 - 3.37 (m, 1H), 1.39 - 1.35 (m, 3H), 1.25 - 1.19 (m, 3H). (3aR,7S,7aS)-7-hydroxy-2,2-dimethyltetrahydro-6H-[1,3]dioxolo[4,5-c]pyran-6-one [00468] Step 2. To the mixture of (3aR,7S,7aS)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5- c]pyran-6,7-diol (53.0 g, 279 mmol, 1.00 eq) and Na2CO3 (44.3 g, 418 mmol, 1.50 eq) in DCM (300 mL) was added Br2 (66.8 g, 418 mmol, 21.5 mL, 1.50 eq) at 15 - 25 °C. The mixture was stirred at 25°C for 3 hrs. TLC (Petroleum ether/Ethyl acetate = 1/1, PMA) showed most of the starting material (Rf = 0.30) was consumed and one main spot (Rf = 0.50) was formed. The mixture was filtered and the filtrate was washed with saturated Na2S2O3 aqueous solution (0.50 M, 500 mL) and brine (300 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue (60.0 g crude). The crude residue was subjected to silica gel column chromatography (Petroleum ether/Ethyl acetate = from 10/1 to 0/1, Petroleum ether/Ethyl acetate = 1/1, Rf = 0.50) to give (3aR,7S,7aS)-7-hydroxy-2,2-dimethyltetrahydro-6H-[1,3]dioxolo[4,5-c]pyran-6-one (35.0 g, 186 mmol) as a white solid.1H NMR: (400 MHz, CDCl3) δ 4.59 (dd, J = 5.2, 11.2 Hz, 1H), 4.55 - 4.47 (m, 1H), 4.46 - 4.41 (m, 1H), 4.40 - 4.34 (m, 1H), 4.13 (dd, J = 8.0, 11.2 Hz, 1H), 3.50 (br s, 1H), 1.52 (s, 3H), 1.38 (s, 3H). (3aR,7S,7aR)-2,2-dimethyl-6-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl trifluoromethanesulfonate [00469] Step 3. To a solution of (3aR,7S,7aS)-7-hydroxy-2,2-dimethyltetrahydro-6H- [1,3]dioxolo[4,5-c]pyran-6-one (35.0 g, 186 mmol, 1.00 eq) in DCM (525 mL) was added Pyridine (58.9 g, 744 mmol, 60.1 mL, 4.00 eq) and Tf2O (105 g, 372 mmol, 61.4 mL, 2.00 eq) at -20 °C ~ -30 °C under N2. The mixture was stirred at -20 ~ -30 °C for 2 hrs. TLC (Petroleum ether/Ethyl acetate = 1/1, PMA) indicated starting material (Rf = 0.50) was consumed completely and one main new spot (Rf = 0.70) was formed. The mixture was poured into brine (600 mL) and separated. The organic layer was washed with brine (500 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a residue. (3aR,7S,7aR)-2,2-dimethyl-6-oxotetrahydro-4H- [1,3]dioxolo[4,5-c]pyran-7-yl trifluoromethanesulfonate (59.6 g, crude) was obtained as a yellow solid, which was used in the next step without further purification. methyl (2R,3R,4R)-3,4-dihydroxytetrahydrofuran-2-carboxylate Step 4. A mixture of (3aR,7S,7aR)-2,2-dimethyl-6-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7- yl trifluoromethanesulfonate (59.6 g, 186 mmol, 1.00 eq) in HCl/MeOH (595 mL, 1% purity, 12.8 eq) was stirred at 25 °C for 2 hrs. Then to the mixture was added HCl (2 M, 46.5 mL, 0.50 eq) at 25 °C. After heated to 70 °C, the mixture was stirred at 70 °C for 3 hrs. TLC (Petroleum ether/Ethyl acetate = 1/1, PMA) indicated starting material (Rf = 0.70) was consumed completely and one new main spot (Rf = 0.10) formed. The reaction mixture was concentrated under vacuum to remove MeOH and H2O. To the residue was added NaHCO3 solid to adjust pH = 7 ~ 8. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 10/1 to 0/1, Petroleum ether/Ethyl acetate = 1/1, Rf = 0.10) twice to give methyl (2R,3R,4R)-3,4-dihydroxytetrahydrofuran-2-carboxylate (32.0 g, 197 mmol) as colorless oil. HRMS-TOF: m/z = 163.0601 (M+H)+.1H NMR: (400 MHz, DMSO-d6). δ 5.29 (d, J = 6.0 Hz, 1H), 4.99 (d, J = 4.4 Hz, 1H), 4.13 - 4.09 (m, 1H), 4.08 - 4.00 (m, 2H), 3.93 (dd, J = 4.4, 9.0 Hz, 1H), 3.65 (s, 3H), 3.64 - 3.59 (m, 1H). Example 28 1-(tert-butyl)-3-((2S,3R,4R)-4-((tert-butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-yl)- 1H-pyrazol-5-amine (Synthetic Intermediate) 1-(tert-butyl)-3-((2S,3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-yl)- 1H-pyrazol-5-amine (Synthetic Intermediate)
Figure imgf000749_0001
Figure imgf000750_0001
methyl (2R,3R,4R)-4-(benzoyloxy)-3-hydroxytetrahydrofuran-2-carboxylate methyl (2R,3R,4R)-3-(benzoyloxy)-4-hydroxytetrahydrofuran-2-carboxylate [00470] Step 1. To a solution of methyl (2R,3R,4R)-3,4-dihydroxytetrahydrofuran-2-carboxylate (10 g, 61.68 mmol, 1 eq.) in pyridine (100 mL) was added BzCl (3.47 g, 24.67 mmol, 2.86 mL, 0.4 eq.) at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (300 mL) and then was extracted with EtOAc (300 mL * 3). The combined organic layers were washed with 1 M HCl (500 mL*2) and a queous NaCl 500 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.50) to give a mixture of methyl (2R,3R,4R)-4-(benzoyloxy)-3-hydroxytetrahydrofuran-2-carboxylate and methyl (2R,3R,4R)-3-(benzoyloxy)-4-hydroxytetrahydrofuran-2-carboxylate (4.2 g, 62.31% yield, 97.44% purity) as a colorless oil. LC-MS (ESI+) m/z: 267.2 (M+H)+. methyl (2S,3S,4R)-4-(benzoyloxy)-3-fluorotetrahydrofuran-2-carboxylate methyl (2R,3S,4S)-3-(benzoyloxy)-4-fluorotetrahydrofuran-2-carboxylate [00471] Step 2. To a solution of methyl (2R,3R,4R)-4-(benzoyloxy)-3-hydroxytetrahydrofuran-2- carboxylate and methyl (2R,3R,4R)-3-(benzoyloxy)-4-hydroxytetrahydrofuran-2-carboxylate (4.2 g, 15.77 mmol, 1 eq.) in DCM (50 mL) was added DAST (10.17 g, 63.10 mmol, 8.34 mL, 4 eq.) at 0 °C. The mixture was stirred at 25 °C for 2 h. DAST (5.09 g, 31.55 mmol, 4.17 mL, 2 eq.) was added to the mixture at 0 °C, the mixture was stirred at 25 °C for 14 h. The mixture was quenched by saturated Na2CO3 (200 mL) slowly and then was extracted with DCM (300 mL * 3). The combined organic layers were washed with aqueous NaCl 300 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give methyl (2S,3S,4R)-4-(benzoyloxy)-3-fluorotetrahydrofuran-2-carboxylate and methyl (2R,3S,4S)-3- (benzoyloxy)-4-fluorotetrahydrofuran-2-carboxylate (2.8 g, 10.37 mmol, 65.74% yield, 99.34% purity) as a colorless oil. LC-MS (ESI+) m/z: 269.2 (M+H)+. (2S,3S,4R)-3-fluoro-4-hydroxytetrahydrofuran-2-carboxylic acid (2R,3S,4S)-4-fluoro-3-hydroxytetrahydrofuran-2-carboxylic acid [00472] Step 3. To a solution of methyl (2S,3S,4R)-4-(benzoyloxy)-3-fluorotetrahydrofuran-2- carboxylate and methyl (2R,3S,4S)-3-(benzoyloxy)-4-fluorotetrahydrofuran-2-carboxylate (2.4 g, 8.95 mmol, 1 eq.) in THF (20 mL) and H2O (5 mL) was added LiOH•H2O (1.88 g, 44.74 mmol, 5 eq.). The mixture was stirred at 20 °C for 16 h. The mixture was diluted with water (50 mL) and then was adjust PH=3 by HCl (1 M), then the mixture was extracted with EtOAc (50 mL * 3). The combined organic layers were washed with aqueous NaCl 50 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (2S,3S,4R)-3-fluoro-4- hydroxytetrahydrofuran-2-carboxylic acid and (2R,3S,4S)-4-fluoro-3-hydroxytetrahydrofuran-2- carboxylic acid (1.95 g, crude) as a white solid, which was used for next step directly without further purification. methyl (2S,3S,4R)-3-fluoro-4-hydroxytetrahydrofuran-2-carboxylate methyl (2R,3S,4S)-4-fluoro-3-hydroxytetrahydrofuran-2-carboxylate [00473] Step 4. To a solution of (2S,3S,4R)-3-fluoro-4-hydroxytetrahydrofuran-2-carboxylic acid and (2R,3S,4S)-4-fluoro-3-hydroxytetrahydrofuran-2-carboxylic acid (1.4 g, 9.33 mmol, 1 eq.) in MeOH (15 mL) was added H2SO4 (457.38 mg, 4.66 mmol, 248.58 μL, 0.5 eq.). The mixture was stirred at 65 °C for 3 h. The mixture was diluted with water (50 mL) and then the mixture was extracted with EtOAc (50 mL * 3). The combined organic layers were washed with aqueous NaCl 50 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give methyl (2S,3S,4R)-3-fluoro-4-hydroxytetrahydrofuran-2-carboxylate and methyl (2R,3S,4S)-4- fluoro-3-hydroxytetrahydrofuran-2-carboxylate (1.2 g, crude) as a colorless oil, which was used for next step directly without further purification. methyl (2S,3R,4R)-4-((tert-butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-carboxylate methyl (2R,3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-carboxylate [00474] Step 5. To a solution of methyl (2S,3S,4R)-3-fluoro-4-hydroxytetrahydrofuran-2- carboxylate and methyl (2R,3S,4S)-4-fluoro-3-hydroxytetrahydrofuran-2-carboxylate (1.2 g, 7.31 mmol, 1 eq.) in DMF (12 mL) was added DMAP (44.66 mg, 365.56 μmol, 0.05 eq.) and imidazole (995.46 mg, 14.62 mmol, 2 eq.) and then tert-butyldimethylsilyl chloride (2.20 g, 14.62 mmol, 1.80 mL, 2 eq.) was added to the mixture. The mixture was stirred at 20 °C for 16 h. The mixture was diluted with water (50 mL) and then the mixture was extracted with EtOAc (50 mL * 3). The combined organic layers were washed with aqueous NaCl (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, from PE/EtOAc = 1/0 to 20/1, TLC (PMA): PE/EtOAc = 10/1, Rf = 0.48) to give methyl (2S,3R,4R)-4-((tert-butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2- carboxylate and methyl (2R,3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2- carboxylate (503 mg, 1.81 mmol, 24.71% yield) as a colorless oil. 3-((2S,3R,4R)-4-((tert-butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-yl)-3- oxopropanenitrile 3-((2R,3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-yl)-3- oxopropanenitrile [00475] Step 6. n-Butyllithium (2.5 M, 2.16 mL, 3 eq.) was added dropwise to THF (5 mL) under N2 at -72 °C, and then MeCN (221.18 mg, 5.39 mmol, 283.57 μL, 3 eq.) was added dropwise to the mixture, the mixture was stirred for 1 h at -72 °C, and then methyl (2S,3R,4R)-4-((tert- butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-carboxylate and methyl (2R,3S,4S)-3-((tert- butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-carboxylate (500 mg, 1.80 mmol, 1 eq) in THF (2 mL) was added dropwise to the mixture, the mixture was stirred at -72 °C for 1 h under N2 atmosphere. The reaction mixture was quenched by addition saturated NH4Cl (20 mL), and then was extracted with EtOAc (20 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product 3-((2S,3R,4R)- 4-((tert-butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-yl)-3-oxopropanenitrile and 3- ((2R,3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-yl)-3-oxopropanenitrile (430 mg, crude) as a yellow solid, which was used for next step directly without further purification. 1-(tert-butyl)-3-((2S,3R,4R)-4-((tert-butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-yl)- 1H-pyrazol-5-amine (Synthetic Intermediate) 1-(tert-butyl)-3-((2S,3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-yl)- 1H-pyrazol-5-amine (Synthetic Intermediate) [00476] Step 7. To a solution of 3-((2S,3R,4R)-4-((tert-butyldimethylsilyl)oxy)-3- fluorotetrahydrofuran-2-yl)-3-oxopropanenitrile and 3-((2R,3S,4S)-3-((tert- butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-yl)-3-oxopropanenitrile (430 mg, 1.50 mmol, 1 eq.) in i-PrOH (5 mL) was added tert-butylhydrazine;hydrochloride (242.37 mg, 1.95 mmol, 1.3 eq.) and DIEA (251.38 mg, 1.95 mmol, 338.79 μL, 1.3 eq.) .The mixture was stirred at 80 °C for 3 h. The mixture was diluted with water (10 mL) and then the mixture was extracted with EtOAc (10 mL * 3). The combined organic layers were washed with aqueous NaCl 20 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give give a residue. The residue was purified by column chromatography (SiO2, from PE/EtOAc = 1/0 to 5/1, TLC (KMnO4): PE/EtOAc = 3/1, Rf = 0.38) to give 1-(tert-butyl)-3-((2S,3R,4R)-4-((tert- butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-yl)-1H-pyrazol-5-amine and 1-(tert-butyl)-3- ((2S,3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-yl)-1H-pyrazol-5-amine (180 mg, 432.81 μmol, 28.93% yield, 85.97% purity) as a yellow oil. LC-MS (ESI+) m/z: 358.5 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 5.73 (d, J = 2.7 Hz, 1H), 5.09 - 4.70 (m, 2H), 4.56 - 4.45 (m, 1H), 4.32 - 3.66 (m, 2H), 3.50 (br s, 2H), 1.67 - 1.59 (m, 9H), 0.94 - 0.84 (m, 9H), 0.14 - 0.01 (m, 6H). [00477] Additional compounds prepared according to the methods of Example 28, and the methods described herein, are depicted in Table 10 below. Table 10. Additional Exemplary Compounds
Figure imgf000754_0001
Example 29 benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((2R,3R*,4S*)-3-fluoro-4- hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (Synthetic Intermediate) benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((2R,3R*,4R*)-3-fluoro-4- hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (Synthetic Intermediate)
Figure imgf000755_0001
benzyl (1-(tert-butyl)-3-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)-1H- pyrazol-5-yl)carbamate [00478] Step 1. A cold (0 °C) solution of 1-(tert-butyl)-3-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)-1H-pyrazol-5-amine (17.8 g, 52.4 mmol) in acetonitrile (124 mL) was treated with benzyl chloroformate (15.0 mL, 106 mmol). After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 90 minutes. Sodium bicarbonate (14.1 g, 168 mmol) was added in one portion and the suspension was stirred at room temperature for 67 h. The reaction mixture was poured into half-saturated NaHCO3 (800 mL) and extracted with ethyl acetate. The organic layer was washed with brine (400 mL). The aq. phases were back extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dried under high vacuum over the 48 h and used directly in the next step without further analysis. benzyl (1-(tert-butyl)-3-((2S,4R)-4-hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5- yl)carbamate [00479] Step 2. Under an argon atmosphere, the crude benzyl (1-(tert-butyl)-3-((2S,4R)-4-((tert- butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (32.33 g) was diluted with THF (80.0 mL) and cooled to -70 °C. A solution of TBAF (105 mL, 105 mmol) in THF (1.0 M) was slowly added while keeping internal temperature below -65 °C. After the addition was complete, the dry ice bath was removed and the reaction mixture was let warmed to room temperature and stirred for 7 h. The reaction mixture was cooled to 0 °C and poured carefully into a cold stirring mixture of ice and sat. NaHCO3. The material was extracted with ethyl acetate and the organic layer was washed with brine. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified by flash chromatography on silica gel column, eluting with 20% to 100% EtOAc in hexanes. The desired fractions were concentrated in vacuo to afford benzyl (1- (tert-butyl)-3-((2S,4R)-4-hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate as a colorless oil (14.19 g, 75% yield over 2 steps). 1H NMR (400 MHz, CDCl3): δ 7.35-7.38 (m; 5 H); 6.28 (br s; 1 H); 6.25 (br s; 1 H); 5.67 (d; J = 10.89 Hz; 1 H); 5.20 (s; 2 H); 5.07 (dd; J = 9.11; 1.79 Hz; 1 H); 4.42-4.47 (m; 1 H); 3.94-3.99 (m; 2 H); 2.37-2.44 (m; 1 H); 2.31 (d; J = 13.68 Hz; 1 H); 1.58 (s; 9 H). ESI-MS (m/z+): 360.2 [M+H]+. benzyl (S)-(1-(tert-butyl)-3-(4-oxotetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate [00480] Step 3. A solution of benzyl (1-(tert-butyl)-3-((2S,4R)-4-hydroxytetrahydrofuran-2-yl)- 1H-pyrazol-5-yl)carbamate (14.2 g, 39.5 mmol) in dichloromethane (250 mL) was treated with water (0.25 mL, 13.9 mmol) and Dess-Martin Periodinane (24.9 g, 52.9 mmol) at 0 °C. After 20 min, the ice water bath was removed and the reaction was warmed to room temperature. After 2 hours the orange suspension was re-cooled to 0 °C and quenched with a cold sat. solution of 1:1 NaHCO3 / Na2S2O3. The ice water bath was removed and the mixture was stirred for 60 min at room temperature. The suspension was diluted with DCM, the organic phase was separated and washed with sat. NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was placed under high vacuum overnight. The crude material was purified by flash chromatography on silica gel column, eluting with 10% to 30% ethyl acetate in hexanes. The desired fractions were concentrated in vacuo and the resultant pink wet solid was dried under high vacuum. The solid was further purified by trituration with dichloromethane and hexanes to afford benzyl (S)-(1-(tert-butyl)-3-(4-oxotetrahydrofuran-2-yl)-1H-pyrazol-5- yl)carbamate as a beige solid (11.17 grams, 79% yield).1H NMR (400 MHz, CDCl3): δ 7.35-7.39 (m; 5 H); 6.32 (s; 1 H); 6.24 (br s; 1 H); 5.30-5.34 (m; 1 H); 5.20 (s; 2 H); 4.09 (d; J = 16.82 Hz; 1 H); 3.94 (d; J = 16.81 Hz; 1 H); 2.91 (dd; J = 17.97; 7.32 Hz; 1 H); 2.76 (dd; J = 17.95; 7.00 Hz; 1 H); 1.58 (s; 9 H). ESI-MS (m/z+): 358.3 [M+H]+. benzyl (S)-(tert-butoxycarbonyl)(1-(tert-butyl)-3-(4-oxotetrahydrofuran-2-yl)-1H-pyrazol- 5-yl)carbamate [00481] Step 4. In a round bottom flask (500 mL), a mixture of benzyl (S)-(1-(tert-butyl)-3-(4- oxotetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (15.0 g, 42.2 mmol), Di-tert- butyldicarbonate (11.2 g, 50.6 mmol) and 4-Dimethylaminopyridine (516 mg, 4.22 mmol) in DCM (150 mL) was treated with Triethylamine (6.06 mL, 43.5 mmol) at room temperature. No significant exotherm was generated (The internal temperature remained below 22-23 °C). After 90 min, the reaction mixture was poured into a sat. solution of NaHCO3 / water (1:1, 300 mL). More DCM (100 mL) was added for the extraction. After separation of the organic phase, the aq. layer was extracted again with DCM (2 x 50 mL). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The brown oil was dried under high vacuum with gentle heating (< 50 °C) with heat gun. The crude oil (20.9 g) was purified by flash chromatography on SiO2 column. The fractions were selected to afford benzyl (S)-(tert- butoxycarbonyl)(1-(tert-butyl)-3-(4-oxotetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate as an oil. benzyl (S)-(tert-butoxycarbonyl)(1-(tert-butyl)-3-(4-((tert-butyldimethylsilyl)oxy)-2,5- dihydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate [00482] Step 5. In a round bottom flask (1 L), benzyl (S)-(tert-butoxycarbonyl)(1-(tert-butyl)-3- (4-oxotetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (19.2 g, 42.1 mmol) was degassed under vacuum (3 cycles, vacuum / argon). Then, DCM (100 mL) was added and the solution was cooled to 0 °C and successively treated with t-Butyl-dimethylsilyltriflate (13.0 mL, 55.5 mmol) dropwise followed 4-5 min later by a slow addition of Triethylamine (7.97 mL, 57.2 mmol) over 5-10 min by keeping the internal temperature below 5 °C. After 45 min at 0 °C, the reaction was diluted with Heptane (200 mL) and the mixture was quenched with a sat. solution of NaHCO3 / brine (1:1, 200 mL). The organic layer was washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude oil was placed under high vacuum with gentle heating with heat gun (< 50 °C) to afford benzyl (S)-(tert-butoxycarbonyl)(1-(tert-butyl)-3-(4-((tert- butyldimethylsilyl)oxy)-2,5-dihydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate as an oil 1H NMR (400 MHz, CDCl3): δ 7.28-7.32 (m; 3 H); 7.20-7.26 (m; 2 H); 6.01 (s; 1 H); 5.74-5.76 (m; 1 H); 5.15-5.25 (m; 2 H); 4.83 (dq; J = 8.65; 1.93 Hz; 1 H); 4.37-4.49 (m; 2 H); 1.47 (d; J = 7.44 Hz; 9 H); 1.43 (d; J = 3.41 Hz; 9 H); 0.94 (s; 9 H); 0.19-0.21 (m; 6 H). ESI-MS (m/z+): 572.4 [M+H]+. This crude mixture was carried out to the next step without any further purification. benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((2R,3R*)-3-fluoro-4-oxotetrahydrofuran-2- yl)-1H-pyrazol-5-yl)carbamate benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((2R,3R*)-3-fluoro-4-oxotetrahydrofuran-2- yl)-1H-pyrazol-5-yl)carbamate [00483] Step 6. In a round bottom flask (1 L), N-Boc-benzyl (S)-(1-(tert-butyl)-3-(4-((tert- butyldimethylsilyl)oxy)-2,5-dihydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (16.9 g, 29.6 mmol) was degassed under vacuum (3 cycles, vacuum / argon). Then, anhydrous ACN (250 mL) was added and the solution was cooled to -35 to -30 °C. The yellow solution was treated in one portion with SelectFluor (11.0 g, 31.0 mmol). After 5 min, the cooling bath was removed and the reaction was let warmed slowly to 0 °C during 10-15 min. Then, an ice water bath was placed and the reaction was stirred at 0 °C for 1 h. The reaction mixture was poured into a solution of sat. NH4Cl / water / brine (1:1:1, 900 mL), extracted with EtOAc (800 mL), washed with brine (300 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was further dried under high vacuum. The crude brown oil was purified by flash chromatography on a SiO2 column after loading with a mixture of DCM / hexanes (1:2) and eluting from 100% DCM to 5% EtOAc  in DCM, and to 10% EtOAc in DCM. TLC (EtOAc / hexanes (1:2): Rf (compound 7b) = 0.46; Rf (compound 7a) = 0.24). [00484] Benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((2R,3R*)-3-fluoro-4-oxotetrahydrofuran- 2-yl)-1H-pyrazol-5-yl)carbamate (compound 7a) was obtained as light yellow oil (2.51g, 18% yield).1H NMR (400 MHz, CDCl3): δ 7.27-7.32 (m; 3 H); 7.20-7.23 (m; 1 H); 7.16-7.18 (m; 1 H); 6.11 (dd; J = 2.40; 1.09 Hz; 1 H); 5.36-5.41 (m; 1 H); 5.11-5.26 (m; 3 H); 4.34 (dd; J = 17.39; 13.97 Hz; 1 H); 4.07-4.12 (m; 1 H); 1.46 (d; J = 1.42 Hz; 9 H); 1.42 (d; J = 6.69 Hz; 9 H). ESI- MS (m/z+): 494.3 [M+H2O+H]. [00485] Benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((2R,3R*)-3-fluoro-4-oxotetrahydrofuran- 2-yl)-1H-pyrazol-5-yl)carbamate (compound 7b) was obtained as light yellow oil (5.43g, 39% yield).1H NMR (400 MHz, CDCl3): δ 7.28-7.33 (m; 3 H); 7.19-7.25 (m; 2 H); 6.18 (s; 1 H); 5.33 (dd; J = 9.54; 6.24 Hz; 0.5 H); 5.10-5.24 (m; 3.5 H); 4.11-4.23 (m; 2 H); 1.48 (d; J = 2.55 Hz; 9 H); 1.44 (d; J = 6.75 Hz; 9 H). ESI-MS (m/z+): 494.3 [M+H2O+H]; 476.3 [M+H]. benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((2R,3R*,4R*)-3-fluoro-4- hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate [00486] Step 7. In a flamed dried round-bottom flask (250 mL) under an argon atmosphere, a solution of (S)-2-Methyl-CBS-oxazaborolidine (1.80 g, 6.49 mmol) in THF (30.0 mL) was cooled to -70 °C and treated with Borane Dimethyl sulfide complex (551 uL, 5.81 mmol). The dry ice bath was removed and the reaction mixture was allowed to warm to -30 °C. Immediately, the reaction was cooled back to -70 °C. After 15-20 min, a suspension was obtained. Then, a solution of N-Boc-benzyl (1-(tert-butyl)-3-((2R)-3-fluoro-4-oxotetrahydrofuran-2-yl)-1H-pyrazol-5- yl)carbamate (2.51 g, 5.28 mmol) in THF (30.0 mL) was added dropwise over 20-30 min via a cannula to the first solution and the internal temperature was kept below -65 °C. The flask was rinsed with extra THF (3 x 3 mL). The reaction was kept at -70 °C for 5 min. The dry ice bath was removed and the reaction mixture was allowed to warm to 0 °C (At around -50 °C, a solution with a turbidity was observed). After reaching -5 to 0 °C, an ice water bath was placed and the reaction was kept at this temperature for 30 min. Then, the reaction was cooled back to -70 °C, MeOH (4 mL) was added dropwise to quench the reaction. The dry ice bath was replaced with an ice water bath and the reaction mixture was allowed to warm to 0 °C for 15-20 min. A lot of bubbles were observed. Then, the reaction mixture was poured into half-saturated aq. NaHCO3 (500 mL) and extracted with EtOAc (400 mL). The organic layer was separated and washed with brine (200 mL). The aq. phases were back extracted with EtOAc (200 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue was co-evaporated with heptane and placed under high vacuum. The crude was purified by flash chromatography on SiO2 after loading with 100% DCM and eluting from 6% to 50% EtOAc in DCM to afford benzyl (tert- butoxycarbonyl)(1-(tert-butyl)-3-((2R,3R*,4R*)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)-1H- pyrazol-5-yl)carbamate as colorless oil (1.59 g, 63% yield).1H NMR (400 MHz, CDCl3): δ 7.28- 7.33 (m; 3 H); 7.19-7.23 (m; 2 H); 6.16 (s; 1 H); 5.11-5.24 (m; 2.5 H); 5.00-5.06 (m; 1.5 H); 4.46- 4.57 (m; 1 H); 4.13-4.18 (m; 1 H); 3.93-3.99 (m; 1 H); 3.79 (ddd; J = 70.04; 10.88; 3.02 Hz; 1 H); 1.48 (d; J = 4.82 Hz; 9 H); 1.42 (d; J = 2.97 Hz; 9 H). ESI-MS (m/z+): 478.3 [M+H]+. [00487] The exemplary compounds shown below were synthesized using the methods of Example 29, and the methods described herein.
Figure imgf000760_0001
Figure imgf000761_0001
Example 30 rel- benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((1S,2R,3S)-2-fluoro-3- hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (Synthetic Intermediate)
Figure imgf000762_0001
[00488] Step 1. In a round bottom flask (500 mL), a mixture of benzyl (1-(tert-butyl)-3-(3- oxocyclopentyl)-1H-pyrazol-5-yl)carbamate (15.0 g, 42.2 mmol), Di-tert-butyldicarbonate (11.2 g, 50.6 mmol) and 4-Dimethylaminopyridine (516 mg, 4.22 mmol) in DCM (150 mL) was treated with Triethylamine (6.06 mL, 43.5 mmol) at room temperature. No significant exotherm was generated (The internal temperature remained below 22-23 °C). After 90 min, the reaction mixture was poured into a sat. solution of NaHCO3 / water (1:1, 300 mL). More DCM (100 mL) was added for the extraction. After separation of the organic phase, the aq. layer was extracted again with DCM (2 x 50 mL). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The brown oil was dried under high vacuum with gentle heating (< 50 °C) with heat gun. The crude oil (20.9 g) was purified by flash chromatography on SiO2 column after loading with DCM / hexanes (1:5; 240 mL) and eluting from 10% EtOAc in hexanes (1 L); 30% (1 L) and 50% (1 L).The fractions were selected by TLC (25% EtOAc in hexanes: Rf (Product) = 0.35) to afford benzyl (tert-butoxycarbonyl)(1-(tert- butyl)-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl)carbamate (20.2 g, 98% yield) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.28-7.31 (m; 3 H); 7.19-7.23 (m; 2 H); 5.89 (s; 1 H); 5.15-5.23 (m; 2 H); 3.42-3.50 (m; 1 H); 2.57 (dd; J = 18.36; 7.81 Hz; 1 H); 2.46 (ddd; J = 18.42; 8.36; 2.41 Hz; 1 H); 2.31-2.39 (m; 2 H); 2.17-2.26 (m; 1 H); 2.00-2.09 (m; 1 H); 1.46 (d; J = 0.92 Hz; 9 H); 1.43 (d; J = 2.43 Hz; 9 H). ESI-MS (m/z+): 456.2 [M+H]+. benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-(3-((tert-butyldimethylsilyl)oxy)cyclopent-2- en-1-yl)-1H-pyrazol-5-yl)carbamate [00489] Step 2. In a round bottom flask (1 L), N-Boc-benzyl (1-(tert-butyl)-3-(3-oxocyclopentyl)- 1H-pyrazol-5-yl)carbamate (19.2 g, 42.1 mmol) was degassed under vacuum (3 cycles, vacuum / argon). Then, DCM (100 mL) was added and the solution was cooled to 0 °C and successively treated with t-Butyl-dimethylsilyltriflate (13.0 mL, 55.5 mmol) dropwise followed 4-5 min later by a slow addition of Triethylamine (7.97 mL, 57.2 mmol) over 5-10 min by keeping the internal temperature below 5 °C. After 45 min at 0 °C, the reaction was diluted with Heptane (200 mL) and the mixture was quenched with a sat. solution of NaHCO3 / brine (1:1, 200 mL). The organic layer was washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude oil was placed under high vacuum with gentle heating with heat gun (< 50 °C) to afford a mixture of 3a and 3b as yellow oil (24.7 g, ratio of 1.7:1). ESI-MS (m/z+): 570.4 [M+H]+. The crude mixture was carried out to the next step without any further purification. rel-benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((1S,2R)-2-fluoro-3-oxocyclopentyl)-1H- pyrazol-5-yl)carbamate (Diastereomer C) [00490] Step 3. In a round bottom flask (1 L), a crude mixture of N-Boc-benzyl (1-(tert-butyl)-3- (3-((tert-butyldimethylsilyl)oxy)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (24.0 g, 42.1 mmol) was degassed under vacuum (3 cycles, vacuum / argon). Then, anhydrous ACN (150 mL) was added and the solution was cooled to -35 to -30 °C. The yellow solution was treated in one portion with SelectFluor (15.2 g, 43.0 mmol). After 5 min, the dry ice bath was removed and the internal temperature slowly increased to 0 °C over 10 min and kept at this temperature with an ice water bath. After 30 min following the end of the addition, the reaction mixture was poured into a sat. solution of NH4Cl / water / brine (1:1:1, 600 mL). The material was extracted with EtOAc (600 mL). The organic phase was separated, washed with brine (200 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was co-evaporated with heptane (2 x 20-30 mL) and placed under high vacuum overnight. The crude oil (21.8 g) was purified by flash chromatography on a SiO2 column after loading with a mixture of DCM / hexanes (1:3) and eluting from 100% hexanes, to 10% EtOAc in hexanes (2 L), to 20% EtOAc in hexanes (3 L), to 30% EtOAc in hexanes (1-2 L). The fractions were selected by TLC. TLC (EtOAc in hexanes (1:2)): Three spots: Rf (Diastereomer A) = 0.57; Rf (Diastereomer B) = 0.49; Rf (Diastereomers C & D) = 0.39. [00491] Diastereomer A was isolated as pure material (3.26 g, 16% yield), a colorless oil that solidified as a wet white solid.1H NMR (400 MHz, CDCl3): δ 7.30-7.32 (m; 3 H); 7.20-7.22 (m; 2 H); 5.89 (d; J = 2.17 Hz; 1 H); 5.16-5.24 (m; 2 H); 5.04 (ddt; J = 51.50; 13.06; 8.01 Hz; 1 H); 3.59-3.64 (m; 1 H); 2.65-2.68 (m; 2 H); 2.52-2.61 (m; 1 H); 2.30-2.42 (m; 1 H); 1.45 (s; 9 H); 1.44 (d; J = 2.41 Hz; 9 H). ESI-MS (m/z+): 474.2 [M+H]. [00492] Diastereomer B was isolated as pure material (2.52 g, 13% yield), a colorless oil.1H NMR (400 MHz, CDCl3): δ 7.29-7.33 (m; 3 H); 7.20-7.23 (m; 2 H); 6.00 (d; J = 2.51 Hz; 1 H); 5.16- 5.24 (m; 2 H); 4.99 (dt; J = 50.54; 10.43 Hz; 1 H); 3.35-3.46 (m; 1 H); 2.32-2.53 (m; 3 H); 2.05- 2.14 (m; 1 H); 1.48 (s; 9 H); 1.44 (d; J = 2.78 Hz; 9 H). ESI-MS (m/z+): 474.2 [M+H] [00493] Diastereomer C and D were isolated as mixture (6.87g) and carried out to next step without any further purification. ESI-MS (m/z+): 474.2 [M+H]. rel- benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((1S,2R,3S)-2-fluoro-3- hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate [00494] Step 4. In a flamed dried round-bottom flask (250 mL) under an argon atmosphere, a solution of (S)-2-Methyl-CBS-oxaborolidine (1.48 g, 5.07 mmol) in THF (24 mL) was cooled to -70 °C and treated with Borane Dimethyl sulfide complex (441 uL, 4.65 mmol). The dry ice bath was removed and the reaction mixture was allowed to warm to -30 °C (controlled temperature measured by thermocouple). Immediately, the reaction was cooled back to -70 °C. After 5-10 min, a solution of diastereomer C and D as mixture (2 g, 4.22 mmol) in THF (24 mL) was added dropwise over 10-12 min via a cannula to the first solution and the internal temperature was kept below -65 °C. The reaction was kept at -70 °C for 5 min. The dry ice bath was removed, and the reaction mixture was allowed to warm to 0 °C. An ice water bath was placed, and the reaction was kept at this temperature for 30 min. Then the reaction was cooled back to -70 °C, MeOH (4 mL) was added dropwise to quench the reaction. The dry ice bath was replaced with an ice water bath and the reaction mixture was allowed to warm to 0 °C for 15-20 min. Then, the reaction mixture was poured into half-saturated aq. NaHCO3 (100 mL) and extracted with EtOAc (200 mL). The aq. phases were back extracted with EtOAc (50 mL, 2X). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The mixture was purified twice over a 220 g silica gel column using a mixture of EtOAc in hexane gradient (0-40%) to afford rel- benzyl (tert-butoxycarbonyl)(1-(tert-butyl)-3-((1S,2R,3S)-2-fluoro-3- hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate as a mixture (1.19 g). ESI-MS (m/z+): 476.2 [M+H]+. [00495] The exemplary compounds shown below were synthesized using the methods of Example 30, and the methods described herein.
Figure imgf000765_0001
Example 31 [00496] Compounds of the present disclosure were tested in a CDK2/Cyclin E fluorescence-based microfluidic mobility shift assay (PerkinElmer). [00497] The active wild type CDK2/Cyclin E complex was purchased from Eurofins (14-475). Compound stocks were prepared in DMSO and were serially diluted into 11 concentrations by 3- fold dilution. Into a 384-well plate (Greiner, 781201) 200 nL compounds were transferred to individual wells prior to adding 15 uL of 1.3x enzyme and ATP solution containing 0.13 nM CDK2/CyclinE and 2660 uM ATP in 1x reaction buffer containing 10 mM Hepes pH 7.5, 0.01 % Brij-35, 10 mM MgCl2, 1 mM EGTA, 0.05 % BSA and 2 mM DTT. Compounds were incubated in the presence of CDK2/Cyclin E complex and ATP for 30 minutes at room temperature. Catalytic reaction was initiated with the addition of 5 uL of a 4x peptide solution containing 6 uM fluorescently label substrate peptide, FL Peptide 18 (aa sequence 5-FAM-QSPKKG, PerkinElmer, 760362) in 1x reaction buffer. [00498] The final reaction components were 0.1 nM CDK2/Cyclin E, 2000 uM ATP and 1.5 uM FL Peptide 18 and 1 % DMSO. Reactions were incubated RT for 20 hr and terminated with 75 uL of a stopping solution containing 0.5 M EDTA. Samples were analyzed using a LabChip EZ reader (PerkinElmer). [00499] Results of the CDK2 Biochemical Caliper Assay are presented in Table 1. Compounds having an IC50 less than or equal to 100 nM are represented as “A”; compounds having an IC50 greater than 100 nM but less than or equal to 250 nM are represented as “B”; compounds having an IC50 greater than 250 nM but less than or equal to1 μM are represented as “C”; and compounds having an IC50 greater than 1 μM but less than or equal to 100 μM are represented as “D”. Absolute values of exemplary compounds of Table 1 are shown in Tables 11-14. Example 32 [00500] Compounds described herein were also tested in a nanoBRET TE Intracellular Kinase Assay. Test compounds were prepared in a DMSO stock solution. 45 uL of stock solution was transferred to a 384 well plate (Greiner, 781201), and a 3-fold 11-point dilution was performed. 293-NB2 cells expressing target tagged with nanoLuciferase were diluted in cell growth media (DMEM + 10% FBS + 1% Pen/Strep media) and a 40 uL cell solution of 7.5E4 cells/mL was seeded in a separate 384 well cell culture plate and incubated overnight at at 37°C/5%CO2/100% humidity. 2uL of 20X Complete NanoBRET K-10 Tracer (Promega NanoBRET) was added to each well of the cell plate except control wells. 80 nL of each concentration of compound was transferred from the compound plate to a corresponding well in the cell culture plate by Echo550 liquid handler. The plates were incubated for 2 hrs at 37°C/5%CO2/100% humidity. 20 uL of 3X Complete Nano-Glo Substrate & ECD NanoLuc Inhibitor (Promega NanoBRET) was added into each well. Chemiluminescence was then read on an EnVision reader (PerkinElmer). [00501] Results of the Cell nanoBRET Assay are presented in Table 1. Compounds having an IC50 less than or equal to 100 nM are represented as “A”; compounds having an IC50 greater than 100 nM but less than or equal to 250 nM are represented as “B”; compounds having an IC50 greater than 250 nM but less than or equal to1 μM are represented as “C”; and compounds having an IC50 greater than 1 μM but less than or equal to 100 μM are represented as “D”. Example 33 [00502] Compounds of the present disclosure were tested in a CDK1/Cyclin B fluorescence-based microfluidic mobility shift assay according to the below procedure. [00503] The active wild type CDK1/Cyclin B complex was purchased from Carna Biosciences (04-102). Compound stocks were prepared in DMSO and were serially diluted into 11 concentrations by 3-fold dilution. Into a 384-well plate (Greiner, 781201) 200 nL compounds were transferred to individual wells prior to adding 15 uL of 1.3x enzyme and ATP solution containing 0.13 nM CDK1/CyclinB and 2660 uM ATP in 1x reaction buffer containing 10 mM Hepes pH 7.5, 0.01 % Brij-35, 10 mM MgCl2, 1 mM EGTA, 0.05 % BSA and 2 mM DTT. Compounds were incubated in the presence of CDK1/Cyclin B complex and ATP for 30 minutes at room temperature. Catalytic reaction was initiated with the addition of 5 uL of a 4x peptide solution containing 6 uM fluorescently label substrate peptide, FL Peptide 29 5-FAM- GGGPATPKKAKKL-CONH2 (aa sequence 5-FAM-GGGPATPKKAKKL, PerkinElmer, 760429) in 1x reaction buffer. The final reaction components were 0.5 nM CDK1/Cyclin B, 2000 uM ATP and 1.5 uM FL Peptide 29 and 1 % DMSO. Reactions were incubated RT for 90 minutes and terminated with 75 uL of a stopping solution containing 0.5 M EDTA. Samples were analyzed using a LabChip EZ reader (PerkinElmer). [00504] Results of the CDK1 Biochemical Caliper Assay were used to calculate selectivities for CDK2/Cyclin E versus CDK1/Cyclin B. Selectivity values for exemplary compounds from Table 1 were calculated as the ratio of the CDK1/Cyclin B IC50 divided by the CDK2/Cyclin E IC50 (from Example 31) as shown in Tables 11, 12, 13, and 14. [00505] The below Tables show potency (CDK2/E IC50) and selectivity (CDK2/E vs CDK1/B) values for exemplary sets of compounds from Table 1 that differ in stereochemistry and fluorine substituent positions within each set. Surprisingly, for all examined cases, the addition of the fluorine substituent in a specific position on, and particular stereochemistry about, the cyclopentyl ring demonstrated a significant increase in selectivity for CDK2/Cyclin E over CDK1/Cyclin B (and the highest selectivity in each set), while maintaining favorably low (i.e., most potent) CDK2/Cyclin E IC50 values. Without wishing to be bound by theory, it will be appreciated that better selectivity allows for a potentially greater therapeutic window such that off-target effects (e.g., toxicity) can be minimized, resulting in a better-tolerated agent. As set forth below in Tables 11-14, forexample, compounds that exhibit the highest potency and greatest selectivity are those compounds having a structure such as that depicted in Formulas XXVI-c and XXVII-c. Table 11.
Figure imgf000768_0001
Figure imgf000769_0001
Table 12.
Figure imgf000770_0001
Table 13.
Figure imgf000771_0001
Table 14.
Figure imgf000772_0001
INCORPORATION BY REFERENCE
[00506] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS
[00507] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
[00508] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

CLAIMS What is claimed is: 1. A compound of formula I:
Figure imgf000774_0001
or a pharmaceutically acceptable salt thereof, wherein: Q is L1; CyA is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyA is substituted with m instances of RA in addition to Q and CyB; CyB is represents a
Figure imgf000774_0002
covalent bond to CyA and
Figure imgf000774_0003
represents a covalent bond to P; P is L2-RP; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to L2; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q; RC is L3-RC1 or L3-H; RC1 is C1–4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each instance of RA, RB is independently R1 or R2, wherein RA is substituted by qA instances of R3, RB is substituted by qB instances of R3, or two instances of RA, two instances of RB, two instances of RC, an instance of RA and an instance of RL, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each of L1, L2, and L3 is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1–6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1–6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of m, n, p, qA, qB, qP, r, and t is independently 0, 1, 2, 3, or 4.
2. A compound of formula II or III:
Figure imgf000777_0001
or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, NRX, and S; Y is selected from O, NRY, and S; each instance of RX and RY is independently R; Q is L1; CyB is
Figure imgf000777_0002
represents a covalent bond to X; RP is a group selected from C1-8 aliphatic, a saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to X or Y; RP1 is R3; CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q; RC is L3-RC1 or L3-H; RC1 is C1–4 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RC1 is substituted with 0-4 instances of a group independently selected from halogen, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each instance of RB is independently R1 or R2, wherein RB is substituted by qB instances of R3, or two instances of RB, two instances of RC, or an instance of RC and an instance of RL are taken together with their intervening atoms to form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with r instances of R3; each of L1, L2, and L3 is independently a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -NHC(O)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1-6 aliphatic; each instance of RL is independently R1 or R2, and is substituted by t instances of R3; each instance of R1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; each instance of R2 is independently C1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R3 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or an optionally substituted group selected from C1–6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1–6 aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4- 7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, qB, qP, r, and t is independently 0, 1, 2, 3, or 4.
3. The compound of claim 1 or 2, wherein P is selected from -ORP, -NHRP-, -SRP, - NHC(O)NHRP, -OC(O)NHRP, and -NHC(O)ORP.
4. The compound of any one of claims 1-3, wherein RP is an optionally substituted group selected from C1–6 aliphatic and a saturated or partially unsaturated 3-7 membered carbocyclic ring.
5. The compound of any one of claims 1-4, wherein CyC is a 5-6 membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur.
6. The compound of any one of claims 1-5, wherein Q is selected from -NH-,
Figure imgf000780_0001
,
Figure imgf000780_0002
, , represents a covalent bond to CyA and
Figure imgf000780_0003
represents a covalent bond to CyC.
7. The compound of any one of claims 1-6, wherein Q is -NH-.
8. The compound of any one of claims 1 and 3-7 , wherein CyA is a heteroarylene having 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur.
9. The compound of any one of claims 1 and 3-8 , wherein CyA is selected from:
Figure imgf000780_0007
, , , , , ,
Figure imgf000780_0004
, wherein
Figure imgf000780_0006
represents a covalent bond to Q and represents a covalent bond to CyB.
10. The compound of any one of claims 1-9, wherein n is 0, 1, 2, 3, or 4
11. The compound of claim 1, wherein the compound is of formula XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, or XXVII-c:
Figure imgf000780_0005
Figure imgf000781_0001
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1, wherein the compound is of formula XXVI-c:
Figure imgf000781_0002
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1, wherein the compound is of formula XXVII-c:
Figure imgf000781_0003
or a pharmaceutically acceptable salt thereof.
14. The compound of any one of claims 11 to 13, wherein RP is a group selected from phenyl, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RP is substituted with qP instances of RP1 in addition to L2.
15. The compound of any one of claims 11 to 13, wherein RP is C1-3 aliphatic substituted with qP instances of RP1
16. The compound of any one of claims 11 to 13, wherein RP is -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, or -CH2CH(CH3)2, -C(CH3)3,
Figure imgf000782_0004
,
17. The compound of any one of claims 11 to 13, wherein RP is
Figure imgf000782_0005
18. The compound of any one of claims 11 to 13 or claim 17 wherein RP is
Figure imgf000782_0006
,
Figure imgf000782_0001
19. The compound of any one of claims 11 to 13, wherein RP is a saturated or partially unsaturated 4-14 membered carbocyclic ring substituted with qP instances of RP1.
20. The compound of any one of claims 11 to 13 or claim 19, wherein RP is a saturated or partially unsaturated 4 membered carbocyclic ring substituted with qP instances of RP1.
21. The compound of any one of claims 11 to 13 or claims 19 to 20, wherein RP is
Figure imgf000782_0002
Figure imgf000782_0003
.
22. The compound of any one of claims 11 to 13or claims 19 to 20, wherein RP is
Figure imgf000783_0001
,
Figure imgf000783_0002
23. The compound of any one of claims 11 to 13, wherein RP is a phenyl ring substituted with qP instances of RP1.
24. The compound of any one of claims 11 to 13, wherein RP is an 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1.
25. The compound of any one of claims 11 to 13or claim 24, wherein RP is an 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1.
26. The compound of claim any one of claims 11 to 13 or claims 24 to 25, wherein RP is
Figure imgf000783_0003
27. The compound of any one of claims 11 to 13, wherein RP is an 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1.
28. The compound of any one of claims 11 to 13or 25, wherein RP is an optionally substituted 5- membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1.
29. The compound of any one of claims 11 to 13or claims 27-28, wherein RP is
Figure imgf000784_0002
,
Figure imgf000784_0001
.
30. The compound of any one of claims 11 to 13or 27, wherein RP is an 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1.
31. The compound of any one of claims 11 to 13, 27, or 30, wherein RP is
Figure imgf000784_0003
32. The compound of any one of claims 11 to 13, wherein RP is an 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1.
33. The compound of any one of claims 11 to 13or 32, wherein RP is an optionally substituted 5- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with qP instances of RP1.
34. The compound of any one of claims 11 to 13or 32, wherein RP is an 6-membered heteroaryl ring having 1-2 nitrogen atoms, substituted with qP instances of RP1.
35. The compound of any one of claims 11 to 13or 32, wherein RP is selected from isothiazolyl, pyridinyl, or pyridazinyl, substituted with qP instances of RP1.
36. The compound of any one of claims 11 to 13or 32, wherein RP is
Figure imgf000785_0002
, ,
Figure imgf000785_0001
37. The compound of any one of claims 11-36, wherein Q is a covalent bond, or a C1-5 saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, -NH-, -N(RL)-, -N(RL)C(O)-, -C(O)NH-, -C(O)N(RL)-, -NHS(O)2-, -N(RL)S(O)2-, -S(O)2NH-, -S(O)2N(RL)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; wherein each of said C3-6 cycloalkylene, 3-6 membered heterocycloalkylene, and 5-6 membered heteroarylene is optionally substituted with one instance of R1 or C1–6 aliphatic.
38. The compound of any one of claims 11-37, wherein Q is -O-, -NH-,
Figure imgf000785_0003
,
Figure imgf000785_0005
,–NHC(O)NH-,
Figure imgf000785_0006
represents a covalent bond to CyA and r C
Figure imgf000785_0004
epresents a covalent bond to Cy .
39. The compound of any one of claims 11-38, wherein CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 6-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein CyC is substituted with p instances of RC in addition to Q.
40. The compound of any one of claims 11-39, wherein CyC is a saturated or partially unsaturated 3-14 membered carbocyclic ring.
41. The compound of any one of claims 11-40, wherein CyC is a saturated or partially unsaturated 3-7 membered monocyclic carbocyclic ring.
42. The compound of any one of claims 11-41, wherein CyC is cyclopropyl.
43. The compound of any one of claims 11-39, wherein CyC is a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
44. The compound of any one of claims 11-39, wherein CyC is phenyl.
45. The compound of any one of claims 11-39, wherein CyC is a 6-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
46. The compound of any one of claims 11-38, wherein CyC is a 5-membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen or sulfur.
47. The compound of any one of claims 11-38 or 46, wherein CyC is
Figure imgf000786_0002
Figure imgf000786_0001
48. The compound of any one of claims 11-39 or 45, wherein CyC is a 6-membered heteroaryl ring having 1-3 nitrogen atoms.
49. The compound of any one of claims 11-39, 45, or 48, wherein CyC is pyridyl, pyrimidinyl, or pyridazinyl.
50. The compound of any one of claims 11-39, 45, or 48-49, wherein CyC is
Figure imgf000787_0001
,
Figure imgf000787_0002
51. The compound of any one of claims 11-37 or 43, wherein CyC is a 9-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
52. The compound of any one of claims 11-37, 43, or 49, wherein CyC is a 9-10 membered heteroaryl having 1-3 heteroatoms indepen dently selected from nitrogen, oxygen, and sulfur.
53. The compound of any one of claims 11-37, 43, or 49, wherein CyC is a 9-10 membered heteroaryl having 2-4 nitrogen atoms.
54. The compound of any one of claims 11-37, 43, or 49, wherein CyC is
Figure imgf000787_0004
Figure imgf000787_0003
Figure imgf000788_0001
55. The compound of any one of claims 1-52, wherein the compound is selected from those depicted in Table 1, or a pharmaceutically acceptable salt thereof.
56. A pharmaceutical composition, comprising a compound of any one of claims 1-53, and a pharmaceutically acceptable carrier.
57. A method of inhibiting CDK2 signaling activity in a subject, comprising administering a therapeutically effective amount of a compound of any one of claims 1-53, or the pharmaceutical composition of claim 54, to a subject in need thereof.
58. A method of treating an CDK2-mediated disorder in a subject, comprising administering a therapeutically effective amount of a compound of any one of claims 1-53, or the pharmaceutical composition of claim 54, to a subject in need thereof.
59. A method of treating a disorder in a subject, wherein the disorder is ovarian cancer, endometrial cancer, gastric cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, stomach cancer, sarcoma cancer, liver cancer, esophageal cancer, laryngeal cancer, multiple myeloma, colorectal cancer, rectal cancer, skin cancer, or pancreatic cancer, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-55, or the pharmaceutical composition of claim 56, to a subject in need thereof.
60. The method of claim 59, wherein the bladder cancer is urothelial carcinoma.
61. The method of claim 59, wherein the liver cancer is hepatocellular carcinoma.
62. The method of claim 59, wherein the lung cancer is lung squamous cell carcinoma or nonsmall cell lung cancer.
63. The method of claim 59, wherein the laryngeal cancer is laryngeal squamous cell carcinoma.
64. The method of claim 59, wherein the skin cancer is melanoma.
PCT/US2023/012759 2022-02-11 2023-02-10 Cdk inhibitors and methods of use thereof WO2023154426A1 (en)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US202263309213P 2022-02-11 2022-02-11
US63/309,213 2022-02-11
US202263325284P 2022-03-30 2022-03-30
US63/325,284 2022-03-30
US202263348599P 2022-06-03 2022-06-03
US63/348,599 2022-06-03
US202263397136P 2022-08-11 2022-08-11
US63/397,136 2022-08-11

Publications (1)

Publication Number Publication Date
WO2023154426A1 true WO2023154426A1 (en) 2023-08-17

Family

ID=87564936

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/012759 WO2023154426A1 (en) 2022-02-11 2023-02-10 Cdk inhibitors and methods of use thereof

Country Status (2)

Country Link
TW (1) TW202337434A (en)
WO (1) WO2023154426A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080306069A1 (en) * 2005-01-21 2008-12-11 Astex Therapeutics Limited Pyrazole Derivatives for the Inhibition of CDK'S and GSK'S
WO2020180959A1 (en) * 2019-03-05 2020-09-10 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors
WO2022174031A1 (en) * 2021-02-12 2022-08-18 Relay Therapeutics, Inc. Cdk inhibitors and methods of use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080306069A1 (en) * 2005-01-21 2008-12-11 Astex Therapeutics Limited Pyrazole Derivatives for the Inhibition of CDK'S and GSK'S
WO2020180959A1 (en) * 2019-03-05 2020-09-10 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors
WO2022174031A1 (en) * 2021-02-12 2022-08-18 Relay Therapeutics, Inc. Cdk inhibitors and methods of use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND ANONYMOUS : "2-[(3S,5S)-5-(butoxymethyl)-3methyloxolan-2-yl]-1H-pyrrole", XP093085609, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "6-cyclopropyl-N-ethyl-2-(3ethylcyclopentyl)pyrimidin-4-amine", XP093085611, retrieved from PUBCHEM *

Also Published As

Publication number Publication date
TW202337434A (en) 2023-10-01

Similar Documents

Publication Publication Date Title
AU2022219987A1 (en) Cdk inhibitors and methods of use thereof
EP3968999B1 (en) Fgfr inhibitors and methods of use thereof
EP3322711B1 (en) Hpk1 inhibitors and methods of using same
JP6666147B2 (en) Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use
JP5031760B2 (en) Imidazopyrazine as a protein kinase inhibitor
RU2537945C2 (en) Triazine, pyrimidine and pyridine analogues and use thereof as therapeutic agents and diagnostic samples
JP2021522275A (en) 2-Amino-pyridine or 2-amino-pyrimidine derivative as a cyclin-dependent kinase inhibitor
CN110997677A (en) Btk inhibitors with improved dual selectivity
CA3217856A1 (en) Heterocyclic compounds and methods of use
JP2009511484A (en) Pyrazolopyrimidines as protein kinase inhibitors
KR20140096100A (en) Bicyclic piperazine compounds
JP2010509328A (en) Imidazopyrazine as an inhibitor of protein kinase
JP2011504931A (en) 2-Fluoropyrazolo [1,5-a] pyrimidine as a protein kinase inhibitor
KR20210145787A (en) Compounds targeting PRMT5
JP7384535B2 (en) Quinazoline compounds and their preparation, use and pharmaceutical compositions
EP3952876A1 (en) Heterocyclic compounds and uses thereof
CA3225285A1 (en) Pi3k.alpha. inhibitors and methods of use thereof
WO2022236256A1 (en) Heterocyclic compounds as kinase inhibitors
WO2023154426A1 (en) Cdk inhibitors and methods of use thereof
CN117136052A (en) CDK inhibitors and methods of use thereof
WO2022148317A1 (en) 2-aminopyrimidine compound and pharmaceutical composition thereof and application thereof
CA3225380A1 (en) Heterocyclic compounds as map4k1 inhibitors
US20230312601A1 (en) Thiazolo[5,4-b]pyridine malt-1 inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23753457

Country of ref document: EP

Kind code of ref document: A1