WO2023239629A1 - Compounds and pharmaceutical compositions that degrade cdk2 - Google Patents

Compounds and pharmaceutical compositions that degrade cdk2 Download PDF

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WO2023239629A1
WO2023239629A1 PCT/US2023/024397 US2023024397W WO2023239629A1 WO 2023239629 A1 WO2023239629 A1 WO 2023239629A1 US 2023024397 W US2023024397 W US 2023024397W WO 2023239629 A1 WO2023239629 A1 WO 2023239629A1
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ring
compound
pharmaceutically acceptable
tautomer
stereoisomer
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French (fr)
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Pengyu YANG
Simon Bailey
Andre RICHTERS
Hongfeng Gao
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Plexium, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This disclosure provides compounds and pharmaceutically acceptable salts thereof that are useful as modulators of targeted ubiquitination.
  • the compounds disclosed herein bind to and/or degrade one or more cyclin dependent kinases (CDKs) and, accordingly, are useful in treating abnormal cell growth such as cancer.
  • CDKs cyclin dependent kinases
  • pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts thereof, and methods of using such compounds and their salts in the treatment of various CDK-mediated diseases or disorders.
  • Cyclin-Dependent Kinases and related serine/threonine protein kinases are important cellular enzymes that perform essential features in regulating cell division and proliferation.
  • CDKs 1-4, 6, 10, and 11 have been reported to play a direct role in cell cycle progression whereas CDKs 3,5, and 7-9 may play an indirect role (e.g., through activation of other CDKs, regulation of transcription or neuronal functions).
  • CDK2 Overexpression of CDK2 is associated with abnormal regulation of the cell -cycle. Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed in cancer. Such overexpression has been associated with poor outcomes in breast cancer including triple negative breast cancer.
  • Ubiquitin-Proteasome Pathway is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.
  • E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See e.g., Li et al. “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling.” PLOS One 2008, (3) 1487; Bemdsen et al. “New insights into ubiquitin E3 ligase mechanism” Nat. Struct. Mol. Biol. 2014, 21:301; Deshaies et al.
  • UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation.
  • the pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair, and biogenesis of organelles.
  • cystic fibrosis including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome
  • Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair, and biogenesis of organelles.
  • the UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome- dependent degradation.
  • Compounds that act as molecular glues can induce or stabilize protein-protein interactions between a target protein and an E3 ubiquitin ligase ligand, leading to protein ubiquitination and subsequent proteasome-mediated degradation via the recruitment to E3 ubiquitin ligase and subsequent ubiquitination.
  • These drug-like molecules offer the possibility of temporal control over protein expression.
  • Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins. See e.g., Crews, Chem. & Biol. 2010, 17 (6): 551; Schneekloth and Crews, Chem Bio Chem., 2005, 6 (1): 40.
  • CDKs cyclin dependent kinases
  • An advantage of the compounds provided herein is that a broad range of pharmacological activities are possible, consistent with the degradation/inhibition of CDKs and modulation of targeted ubiquitination.
  • the disclosure provides methods of using the compounds described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., breast cancer, in a subject in need thereof.
  • the disclosed compounds are represented by formula I’: r or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein
  • Y is N or C-V
  • Ring C is wherein the solid bond 1 attaches Ring C to Y and the solid bond 2 attaches Ring C to L;
  • V is selected from hydrogen, deuterium, and fluoro
  • X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
  • R 12 and R 12 are independently selected from hydrogen, deuterium, and fluoro; or R 12 and R 12 together are oxo; n is 0 or 1; p is 0 or 1;
  • R 3 and R 4 are independently hydrogen or CH3; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
  • R 13 is hydrogen or -CH 2 -OR 14 ;
  • R 14 is -C(O)-R 15 or -P(O)(OR 16 ) 2 ;
  • R 15 is C1-C4 alkyl or C1-C4 alkoxy; each R 16 is independently hydrogen or C1-C4 alkyl;
  • Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
  • Y 1 is -O- or -CH2-
  • Z is -O- or -CH2-
  • R 1 and R 2 are independently selected from hydrogen, Ci-Cg alkyl, I -(C3-Cg cycloalkyl), and L 1 -(4- to 7-membered heterocycloalkyl), wherein said Ci-Cg alkyl, G-Cg cycloalkyl and 4- to 7- membered heterocycloalkyl is optionally substituted by one to four R 8 ;
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 3- to 11- membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N, N(R 17 ), and S(O) m as a ring member, wherein said 3- to 11-membered ring is optionally substituted by one to four R 8 ;
  • R 17 is hydrogen, C1-C4 alkyl, or C(O)-(Ci-C4 alkyl);
  • R 18 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C(O)-(Ci-C4 alkyl); m is 0, 1 or 2;
  • L 1 is a bond or a C1-C2 alkylene optionally substituted with one to four R 9 ;
  • Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein Ring A is substituted with from 0 to 3 R 7 moieties, and each R 7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n ;
  • R 10 and R 11 are each independently H or C1-C4 alkyl
  • Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein Ring B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n , or Ring B is absent; a, b, and c are independently 0 or
  • R 9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
  • Ring C is wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
  • V is selected from hydrogen, deuterium, and fluoro
  • X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
  • R 12 and R 12 are independently selected from hydrogen, deuterium, and fluoro; or R 12 and R 12 together are oxo; n is 0 or 1; p is 0 or 1;
  • R 13 is hydrogen or -CH2-OR 14 ;
  • R 14 is C(O)-R 15 or -P(O)(OR 16 ) 2 ;
  • R 15 is C1-C4 alkyl or C1-C4 alkoxy; each R 16 is independently hydrogen or C1-C4 alkyl;
  • Ring D is selected from G-Go aryl ring, C5-G cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
  • R 1 and R 2 are independently selected from hydrogen, Ci-Cg alkyl, L’-G-G, cycloalkyl, and L 1 -4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, -G, cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by one to four R 8 ;
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 4- to 6- membered ring optionally containing an additional heteroatom selected from O, N, N(R 17 ), and S(O) m as a ring member, wherein said 4- to 6-membered ring is optionally substituted by one to four R 8 ;
  • R 17 is hydrogen, Ci-G alkyl, or C(O)-Ci-C4 alkyl
  • R 18 is hydrogen, Ci-G alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
  • L 1 is a bond or a G-G alkylene optionally substituted with one to four R 9 ;
  • Ring A is selected from Cg-Go aryl ring; G-G cycloalkyl ring; G-G cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R 7 moieties, and each R 7 is independently selected from halo, hydroxy, cyano, G-G alkyl, G-G fluoroalkyl, G-G alkoxy, G-G fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n ;
  • R 10 and R 11 are each independently H or G-G alkyl
  • Ring B is selected from G-Go aryl; G-G cycloalkyl ring; G-G cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, G-G alkyl, G-G fluoroalkyl, G-G alkoxy, G-G fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n , or B is absent; a, b, and c are independently 0 or 1 ; each of W and W 2 , if present, is independently
  • the disclosed compounds are represented by formula IA: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
  • V is hydrogen
  • X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
  • R 12 and R 12 are hydrogen, or R 12 and R 12 together are oxo; n is 0 or 1; p is 0 or 1;
  • R 13 is hydrogen
  • Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4 to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 5-10 membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
  • Z is -O- or -CH2-
  • R 1 and R 2 are independently selected from hydrogen, Ci-Cg alkyl, L 1 -(C3-Cg cycloalkyl), and L 1 -(4- to 7-membered heterocycloalkyl), wherein said Ci-Cg alkyl, C’s-Cg cycloalkyl and 4- to 7- membered heterocycloalkyl is optionally substituted by one to four R 8 ;
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 3- to 11- membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N(R 17 ), and S(O) m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R 8 ;
  • R 17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl;
  • R 18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
  • L 1 is a bond or a C1-C2 alkylene optionally substituted with one to four R 9 ;
  • Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to
  • R 10 and R 11 are each independently H or C1-C4 alkyl
  • B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to
  • W 2 if present, is Ci-Cg alkylene optionally substituted with 1 to 3 R 9 and W 1 , if present, is -C(O)-, O, S, NR 18 or Ci-Cg alkylene optionally substituted with 1 to 3 R 9 provided that the aggregate sum of carbon atoms in W 1 and W 2 is no more than 4; and
  • R 9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy; or when W is absent then W 1 is C4-C8 heteroalkylene containing 1 to 3 oxygen atoms.
  • the disclosed compounds are represented by formula IB:
  • V is hydrogen
  • X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
  • R 12 and R 12 are hydrogen, or R 12 and R 12 together are oxo; n is 0 or 1; p is 0 or 1;
  • R 13 is hydrogen
  • Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 5-10 membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
  • Z is -O- or -CH2-
  • R 1 and R 2 are independently selected from hydrogen, Ci-Cg alkyl, L'-G-Cg cycloalkyl, and L 1 -4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, C -Cg cycloalkyl and 4- to 7-membered heterocycloalkyl is optionally substituted by one to four R 8 ;
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 3- to 11- membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N(R 17 ), and S(O) m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R 8 ;
  • R 17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl
  • R 18 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
  • L 1 is a bond or a C1-C2 alkylene optionally substituted with one to four R 9 ;
  • L is represented by the formula: wherein:
  • Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to
  • R 10 and R 11 are each independently H or C1-C4 alkyl
  • B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to
  • W 2 if present, is Ci-Cg alkylene optionally substituted with 1 to 3 R 9 and W 1 , if present, is -C(O)-, O, S, NR 18 or Ci-Cg alkylene optionally substituted with 1 to 3 R 9 provided that the aggregate sum of carbon atoms in W 1 and W 2 is no more than 4;
  • R 9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy; and when W 2 is absent then W 1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms.
  • the disclosed compounds are represented by formula III: or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein
  • Y is N or C-V
  • Ring C is wherein the solid bond 1 attaches Ring C to Y and the solid bond 2 attaches Ring C to L;
  • V is selected from hydrogen, deuterium, and fluoro
  • X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and Cwfluoroalkyloxy;
  • R 12 and R 12 are independently selected from hydrogen, deuterium, and fluoro; or R 12 and R 12 together are oxo; n is 0 or 1; p is 0 or 1;
  • R 3 and R 4 are independently hydrogen, halo, or CH3; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
  • Y 1 is -O- or -CH2-
  • Z 1 is -O-, and R 5 is selected from Cg-Cio aryl; 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms; C3-C6 cycloalkyl ring; and C1-C3 alkyl optionally substituted with C1-C3 alkoxy or phenyl; wherein the Cg-Cio aryl and the 6-membered heteroaryl ring are substituted with 0 to 2 R 6 , and each R 6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyl; or -Z’-IV is hydrogen;
  • R 13 is hydrogen or -CH2-OR 14 ;
  • R 14 is C(O)-R 15 or -P(O)(OR 16 ) 2 ;
  • R 15 is C1-C4 alkyl or C1-C4 alkoxy; each R 16 is independently hydrogen or C1-C4 alkyl;
  • Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
  • R 18 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C(O)-Ci-C4 alkyl;
  • L is represented by the formula: wherein: Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R 7 moieties, and each R 7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n ;
  • R 10 and R 11 are each independently H or C1-C4 alkyl
  • Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n , or B is absent; a, b, and c are independently 0 or 1
  • R 9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
  • X is hydrogen or halo. In some embodiments, X is fluoro.
  • Ring D is a Cg-Cio aryl ring. In some embodiments, Ring D is a Cs-Cg cycloalkyl ring. In some embodiments, Ring D is a 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms. In some embodiments, Ring D is a 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms. In some embodiments, Ring D is absent. In some embodiments, Ring D is absent,
  • Ring A is a 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring
  • a is zero in L, and the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is represented by formula Ila:
  • a and c are zero in L, and the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is represented by formula lib:
  • B is a 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, -NR 10 R n , and -C(O)NR 10 R n [0026]
  • L is
  • a and c are zero and B is absent in L, and the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is represented by formula lie:
  • b is 1 and W 1 is O or CH2.
  • L is
  • b is 0. In some embodiments, L is
  • b is 1 and W 1 is -CH2-.
  • L is
  • b is 0. In some embodiments, L is .
  • n is 0. In some embodiments, n is 1. In some embodiments, p is 1.
  • R 1 and R 2 are independently selected from hydrogen and Ci-Cg alkyl.
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 3 - to 11 -membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N, N(R 17 ), and S(O) m as a ring member, wherein said 4- to 6-membered ring is optionally
  • Z is -O-. In some embodiments, Z is -CH2-. In some embodiments, Y is C-V. In some embodiments, V is hydrogen. In some embodiments, Y is N. In some embodiments, Y 1 is -CH2-.
  • R 5 is Cg-Cw aryl substituted with 0 to 2 R 6 . In some embodiments, R 5 is
  • R 5 is .
  • -Z’-R 2 is hydrogen.
  • the compound is selected from Table 1 or Table 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
  • the compounds as described herein modulate CDK2. In some embodiments, the compounds as described herein bind to CDK2. In some embodiments, the compounds as described herein degrade CDK2. [0038] In some embodiments, this disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound, such as an amount effective for modulating or degrading CDK2.
  • this disclosure provides a method for modulating or degrading CDK2, which method comprises contacting CDK2 with a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions wherein CDK2 is bound to said compound and modulated or degraded.
  • a compound as described herein e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions wherein CDK2 is bound to said compound and modulated or degraded.
  • this disclosure provides a method for modulating or degrading CDK2 in a subject, which method comprises administering to said subject a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient, under conditions wherein said CDK2 is bound to said compound and modulated or degraded.
  • a compound as described herein e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient, under conditions wherein said CDK2 is bound to said compound and modulated or degraded.
  • this disclosure provides a method for treating a CDK2 dependent disease or disorder, or a disease or disorder that is mediated, at least in part by, CDK2, or a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2, in a subject in need thereof, which method comprises administering to said subject an effective amount of a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
  • a compound as described herein e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound
  • this disclosure provides a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, for use in treating a CDK2 dependent disease or disorder, or a disease or disorder that is mediated, at least in part by, CDK2, or is a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2.
  • CCNE1 cyclin El
  • CCNE2 cyclin E2
  • this disclosure provides a use of a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, in the preparation of a medicament for treating a CDK2 dependent disease or disorder, or a disease or disorder that is mediated, at least in part by, CDK2, or is a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2.
  • CCNE1 cyclin El
  • CCNE2 cyclin E2
  • the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2 is one or more selected from liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein- Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma.
  • the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2 is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma.
  • the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2 is selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic r
  • this disclosure provides a method for treating hyperplasias in a subject in need thereof which method comprises administering to said subject an effective amount of a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
  • a compound as described herein e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
  • this disclosure provides a method for treating cancer in a subject in need thereof which method comprises administering to said subject an effective amount of a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
  • a compound as described herein e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
  • the cancer treated in the methods described herein is breast cancer, such as triple negative breast cancer.
  • the methods disclosed herein further comprise administering to the subject one or more additional therapies or therapeutic agents.
  • the one or more additional therapies or therapeutic agents are one or more selected from surgery, radiotherapy, endocrine therapy, biologic response modifiers, hyperthermia and cryotherapy, agents to attenuate any adverse effects, alkylating drugs, antimetabolites, purine antagonists and pyrimidine antagonists, spindle poisons, podophyllotoxins, antibiotics, nitrosoureas, inorganic ions, enzymes, and hormones.
  • This disclosure provides compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions to treat diseases, disorders, or conditions mediated, at least in part, by CDK2.
  • CDK2 diseases, disorders, or conditions mediated, at least in part, by CDK2.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -C(O)NH2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.
  • C u-V indicates that the following group has from u to v carbon atoms.
  • Ci-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • compositions and methods when used to define compositions and methods means that the compositions and methods so modified include at least the recited elements and do not include other materials or steps that would materially affect the basic and novel characteristic(s) of the claimed disclosure.
  • a composition or method “consisting essentially of’ recited elements could include other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure.
  • compositions and methods when used to define compositions and methods means that the compositions and methods so modified include the recited elements and do not include more than trace amounts of other ingredients or do not include other substantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl).
  • alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3 -hexyl, and 3 -methylpentyl.
  • butyl includes n-butyl (i.e., -(CFE CFfi), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., - CH 2 CH(CH 3 )2), and tert-butyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CFE CFfi) and isopropyl (i.e., -CH( CThfi).
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc.
  • an “alkylene” group or an “alkylenyl” group for example, methylenyl, ethylenyl, and propylenyl
  • an “arylene” group or an “arylenyl” group for example, phenylenyl or napthylenyl, or quinolinyl for heteroarylene
  • Alkenyl refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 12 carbon atoms (i.e., C2-12 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl).
  • alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3 -butadienyl).
  • Alkynyl refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 12 carbon atoms (i.e., C2-12 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl).
  • alkynyl also includes those groups having one triple bond and one double bond.
  • Alkoxy refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1 ,2-dimethylbutoxy .
  • Alkylthio refers to the group “alkyl-S-”.
  • Alkylsulfmyl refers to the group “alkyl-S(O)-”.
  • Alkylsulfonyl refers to the group “alkyl-S(O)2-”.
  • Alkylsulfonylalkyl refers to -alkyl-S(O)2-alkyl.
  • acyl refers to a group -C(O)R y , wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group -C(0)NR y R z and an “N- amido” group which refers to the group -NR y C(0)R z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein, or R y and R z are taken together to form a cycloalkyl or heterocyclyl; each of which may be unsubstituted or substituted, as defined herein.
  • Amino refers to the group -NR y R z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • “Amidino” refers to -C(NR y )(NR z 2), wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., Cg-20 aryl), 6 to 12 carbon ring atoms (i.e., Cg-i2 aryl), or 6 to 10 carbon ring atoms (i.e., Cg-io aryl).
  • Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl.
  • Aryl does not encompass or overlap in any way with heteroaryl defined below.
  • the resulting ring system is heteroaryl regardless of point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of point of attachment. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkyl regardless of point of attachment.
  • Carbamoyl refers to both an “0-carbamoyl” group which refers to the group -0-C(0)NR y R z and an “N-carbamoyl” group which refers to the group -NR y C(0)0R z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • Carboxyl ester or “ester” refer to both -0C(0)R x and -C(0)0R x , wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • the term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring).
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-14 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl).
  • Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like.
  • cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.
  • cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5 ]undecanyl .
  • Imino refers to a group -C(NR y )R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • “Imido” refers to a group -C(O)NR y C(O)R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • Halogen refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.
  • a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen.
  • haloalkyl examples include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3 -bromo-2 -fluoropropyl, 1,2-dibromoethyl, and the like.
  • Haloalkoxy refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.
  • Hydroxyalkyl refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.
  • “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom(s), are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom.
  • the term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms.
  • 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • heteroalkyl groups include, e.g., ethers (e.g., -CH2OCH3, - CH(CH 3 )OCH 3 , -CH2CH 2 OCH 3 , -CH2CH2OCH2CH 2 OCH 3 , etc ), thioethers (e.g., -CH 2 SCH 3 , - CH(CH 3 )SCH 3 , -CH2CH2SCH 3 ,-CH2CH2SCH2CH 2 SCH 3 , etc ), sulfones (e.g, -CH 2 S(O) 2 CH 3 , - CH(CH 3 )S(O) 2 CH 3 , -CH2CH 2 S(O)2CH 3 , -CH2CH2S(O)2CH2CH 2 OCH 3 , etc ), and amines (e.g., - CH 2 NR y CH 3 , -CH(CH 3 )NR y CH 3 , -CH2CH 2CH
  • Heteroaryl refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3 -8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxid
  • fused- heteroaryl rings examples include, but are not limited to, benzo [d]thiazolyl, quinolinyl, isoquinolinyl, benzo [b]thiophenyl, indazolyl, benzo [d] imidazolyl, pyrazolo[l,5-a]pyridinyl, and imidazo[l,5- a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.
  • Heterocyclyl used interchangeably with “heterocycloalkyl”- refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heterocyclyl includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups.
  • Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).
  • the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen.
  • ring carbon atoms i.e., C2-20 heterocyclyl
  • 2 to 12 ring carbon atoms i.
  • heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-
  • heterocyclyl also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom.
  • spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.4]octanyl, and 6-oxa-l-azaspiro[3.3]heptanyl.
  • fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3- c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.
  • “Sulfonyl” refers to the group -S(O)2R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • “Sulfinyl” refers to the group -S(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.
  • “Sulfonamide” refers to the groups -SC>2NR y R z and -NR y SC>2R z , where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
  • substituted means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl
  • substituted includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(0)R h , “substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with -C(O)R g , -C(O)OR g , -C(O)NR g R h , -CH 2 SO 2 R
  • substituted also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R g and R h are taken together with the atoms to which they are attached to form a heterocyclyl ring unsubstituted or substituted with oxo, halo, or alkyl unsubstituted or substituted with oxo, halo, amino, hydroxy, or alk
  • impermissible substitution patterns e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms. Such impermissible substitution patterns are well known to the skilled artisan.
  • substituted may describe other chemical groups defined herein.
  • any compound or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds (i.e., the amount of labeled forms is above the natural abundance for that form). These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • isotopically enriched analogs includes “deuterated analogs” of compounds described herein in which one or more hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and/or an improvement in therapeutic index.
  • An 18 F, 3 H, or n C labeled compound may be useful for PET or SPECT or other imaging studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino, and/or carboxyl groups, or groups similar thereto.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing or suitable for use in a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • pharmaceutically acceptable salt of a given compound refers to salts that exhibit the intended efficacy of the reference compound and which are not biologically or otherwise undesirable, e.g., due to toxicity or other properties.
  • “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt
  • a suitable organic solvent may be used to prepare nontoxic pharmaceutically acceptable addition salts.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases.
  • Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkyl amines (i.e., NfLfalkyl)).
  • dialkyl amines i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NfLfsubstitiitcd alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkylfi).
  • alkenyl amines i.e., NH2(alkenyl)
  • dialkenyl amines i.e., HN(alkenyl)2)
  • trialkenyl amines i.e., N(alkenyl)3
  • substituted alkenyl amines i.e., NH2(substituted alkenyl)
  • di(substituted alkenyl) amines i.e., HN(substituted alkenyl ⁇
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • Tautomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
  • the compounds described herein, or their pharmaceutically acceptable salts may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S')- or, as (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms, and various combinations thereof.
  • (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and/or fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable .
  • the present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are non-superimposeable mirror images of one another.
  • ‘Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • Prodrug means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V.
  • Subject refers to a mammal.
  • the mammal can be a human or non-human mammalian organism.
  • a “patient” refers to a human subject.
  • Treating” or “treatment” of a disease or disorder in a subject refers to inhibiting the disease or disorder or arresting its development or ameliorating or causing regression of the disease or disorder.
  • “effective amount” refers to an amount of a compound described herein that is sufficient to achieve the intended effect, such as modulating CDK2 or treating a disease or disorder afflicting a subject.
  • administering refers to any art recognized form of administration to a subject including injection (e.g., intravenous, subcutaneous, intramuscular), oral (including oral gavage), pulmonary, transdermal, sublingual, transmucosal (e.g., vaginal, nasal, etc.), and the like.
  • injection e.g., intravenous, subcutaneous, intramuscular
  • oral including oral gavage
  • pulmonary e.g., transdermal, sublingual
  • transmucosal e.g., vaginal, nasal, etc.
  • ubiquitin ligase refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation.
  • an E3 ubiquitin ligase protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein, and subsequently targets the specific protein substrates for degradation by the proteasome.
  • E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins.
  • the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth.
  • Polyubiquitination marks proteins for degradation by the proteasome.
  • Mono- ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin.
  • different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.
  • this disclosure provides a compound of formula F: r or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
  • Y is N or C-V
  • Ring C is wherein the solid bond 1 attaches Ring C to Y and the solid bond 2 attaches Ring C to L;
  • V is selected from hydrogen, deuterium, and fluoro
  • X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
  • R 12 and R 12 are independently selected from hydrogen, deuterium and fluoro; or R 12 and R 12 together are oxo; n is 0 or 1; p is 0 or 1;
  • R 3 and R 4 are independently hydrogen or CH3; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
  • R 13 is hydrogen or -CH 2 -OR 14 ;
  • R 14 is -C(O)-R 15 or -P(O)(OR 16 ) 2 ;
  • R 15 is C1-C4 alkyl or C1-C4 alkoxy; each R 16 is independently hydrogen or C1-C4 alkyl;
  • Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
  • Y 1 is -O- or -CH 2 -;
  • Z is -O- or -CH 2 -;
  • R 1 and R 2 are independently selected from hydrogen, Ci-Cg alkyl, L 1 -(G-Cg cycloalkyl), and L 1 -(4- to 7-membered heterocycloalkyl), wherein said Ci-Cg alkyl, G-Cg cycloalkyl and 4- to 7- membered heterocycloalkyl is optionally substituted by one to four R 8 ;
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 3- to 11- membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N, N(R 17 ), and S(O) m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R 8 ;
  • R 17 is hydrogen, C1-C4 alkyl, or C(0)-(G-C4 alkyl);
  • R 18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
  • L 1 is a bond or a G-C 2 alkylene optionally substituted with one to four R 9 ;
  • Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R 7 moieties, and each R 7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n ;
  • R 10 and R 11 are each independently H or C1-C4 alkyl
  • Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n , or B is absent; a, b, and c are independently 0 or 1
  • R 9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
  • this disclosure provides a compound of formula I:
  • Ring C is wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
  • V is selected from hydrogen, deuterium, and fluoro
  • X is selected from hydrogen, halo, hydroxy, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, and C1-4 fluoroalkyloxy;
  • R 12 and R 12 are independently selected from hydrogen, deuterium and fluoro or R 12 and R 12 together are oxo; n is 0 or 1; p is 0 or 1;
  • R 13 is hydrogen or -CH2-OR 14 ;
  • R 14 is -C(O)-R 15 or -P(O)(OR 16 ) 2 ;
  • each R 16 is independently hydrogen or C1-C4 alkyl
  • Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4 to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
  • R 1 and R 2 are independently selected from hydrogen, Ci-Cg alkyl, L'-C’s-Cg cycloalkyl, and I -4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, C -Cg cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by one to four R 8 ;
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 4- to 6-membered ring optionally containing an additional heteroatom selected from O, N, N(R 17 ), and S(O) m as a ring member, wherein said 4- to 6-membered ring is optionally substituted by one to four R 8 ;
  • R 17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl
  • R 18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
  • L 1 is a bond or a C1-C2 alkylene optionally substituted with one to four R 9 ;
  • Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R 7 moieties, and each R 7 is independently selected from halo, hydroxy, cyano, C1-4 alkyl, Ci-4fluoroalkyl, C1-4 alkoxy, C1-4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n ;
  • R 10 and R 11 are each independently H or C1-C4 alkyl
  • Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, C 1-4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n , or B is absent; a, b, and c are independently 0 or 1 ; each of W and W 2 , if
  • R 9 is independently selected from halo, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, and C1-4 fluoroalkyloxy.
  • this disclosure provides a compound of formula IA:
  • Ring C is wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
  • V is hydrogen
  • X is selected from hydrogen, halo, hydroxy, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, and C Mfluoroalkyloxy ;
  • R 12 and R 12 are hydrogen or R 12 and R 12 together are oxo; n is 0 or 1; p is 0 or 1;
  • R 13 is hydrogen
  • Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4 to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 5-10 membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
  • R 1 and R 2 are independently selected from hydrogen, Ci-Cg alkyl, L'-C’s-Cg cycloalkyl, and I -4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, C -Cg cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by one to four R 8 ;
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 3 - to 6-membered ring optionally containing an additional heteroatom selected from O, N(R 17 ), and S(O) m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R 8 ;
  • R 17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl
  • R 18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
  • L 1 is a bond or a C1-C2 alkylene optionally substituted with one to four R 9 ;
  • Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 10- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R 7 moieties, and each R 7 is independently selected from halo, hydroxy, cyano, CM alkyl, Ci-4fluoroalkyl, C alkoxy, CM fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n ;
  • R 10 and R 11 are each independently H or C1-C4 alkyl
  • B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11- membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4 to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, CM alkyl, CM fluoroalkyl, CM alkoxy, C 1-4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n , or B is absent; b and c are independently 0 or 1 ;
  • W 2 if present, is Ci-Cg alkylene optionally substituted with 1 to 3 R 9 and W 1 , if present, is -C(O)-, O, S, NR 18 or Ci-Cg alkylene optionally substituted with 1 to 3 R 9 provided that the aggregate sum of carbon atoms in W 1 and W 2 is no more than 4; and
  • R 9 is independently selected from halo, cyano, CM alkyl, CM fluoroalkyl, CM alkoxy, and CM fluoroalkyloxy or when W is absent then W 1 is C4-C8 heteroalkylene containing 1 to 3 oxygen atoms.
  • Ring C is wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
  • V is hydrogen;
  • X is selected from hydrogen, halo, hydroxy, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, and C wfluoroalkyloxy ;
  • R 12 and R 12 are hydrogen or R 12 and R 12 together are oxo; n is 0 or 1; p is 0 or 1;
  • R 13 is hydrogen
  • Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4 to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 5-10 membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
  • R 1 and R 2 are independently selected from hydrogen, Ci-Cg alkyl, L'-C’s-Cg cycloalkyl, and I -4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, C -Cg cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by one to four R 8 ;
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 3 - to 6-membered ring optionally containing an additional heteroatom selected from O, N(R 17 ), and S(O) m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R 8 ;
  • R 17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl
  • R 18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
  • L 1 is a bond or a C1-C2 alkylene optionally substituted with one to four R 9 ;
  • Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 10- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R 7 moieties, and each R 7 is independently selected from halo, hydroxy, cyano, C1-4 alkyl, Ci-4fluoroalkyl, C1-4 alkoxy, C1-4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n ;
  • R 10 and R 11 are each independently H or C1-C4 alkyl
  • B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11- membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4 to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, Ci-4fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n , or B is absent; b and c are independently 0 or 1 ;
  • W 2 if present, is Ci-Cg alkylene optionally substituted with 1 to 3 R 9 and W 1 , if present, is -C(O)-, O, S, NR 18 or Ci-Cg alkylene optionally substituted with 1 to 3 R 9 provided that the aggregate sum of carbon atoms in W 1 and W 2 is no more than 4;
  • R 9 is independently selected from halo, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, and C1-4 fluoroalkyloxy; and when W 2 is absent then W 1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms.
  • Y is N or C-V
  • Ring C is wherein the solid bond 1 attaches Ring C to Y and the solid bond 2 attaches Ring C to L;
  • V is selected from hydrogen, deuterium, and fluoro
  • X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and Ci-4fluoroalkyloxy;
  • R 12 and R 12 are independently selected from hydrogen, deuterium, and fluoro; or R 12 and R 12 together are oxo; n is 0 or 1; p is 0 or 1;
  • R 3 and R 4 are independently hydrogen, halo, or CH3; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; Y 1 is -O- or -CH 2 -;
  • Z 1 is -O-, and R 5 is selected from Cg-Cw aryl; 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms; C3-C6 cycloalkyl ring; and C1-C3 alkyl optionally substituted with C1-C3 alkoxy or phenyl; wherein the Cg-Cw aryl and the 6-membered heteroaryl ring are substituted with 0 to 2 R 6 , and each R 6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyl; or -Z ⁇ R 5 is hydrogen;
  • R 13 is hydrogen or -CH 2 -OR 14 ;
  • R 14 is C(O)-R 15 or -P(O)(OR 16 ) 2 ;
  • R 15 is C1-C4 alkyl or C1-C4 alkoxy; each R 16 is independently hydrogen or C1-C4 alkyl;
  • R 18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl;
  • Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
  • Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R 7 moieties, and each R 7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n ;
  • R 10 and R 11 are each independently H or C1-C4 alkyl
  • Ring B is selected from Cg-Cw aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n , or B is absent; a, b, and c are independently 0 or 1 ;
  • R 9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
  • R 12 and R 12 are independently selected from hydrogen, deuterium, and fluoro. In some embodiments, R 12 and R 12 are hydrogen. In some embodiments, R 12 and R 12 are fluoro. In some embodiments, R 12 and R 12 are deuterium. In some embodiments, R 12 and R 12 together are oxo.
  • Ring C is In some embodimetns, Ring C is
  • X is hydrogen or halo. In some embodiments, X is hydrogen. In some embodiments, X is halo. In some embodiments, X is fluoro or chloro. In some embodiments, X is hydrogen, fluoro, or chloro.
  • X is hydroxy. In some embodiments, X is cyano. In some embodiments, X is C1-C4 alkyl. In some embodiments, X is C1-C4 fluoroalkyl. In some embodiments, X is C1-C4 alkoxy. In some embodiments, X is C1-C4 fluoroalkyloxy.
  • Y is C-V. In some embodiments, Y is N.
  • V is hydrogen. In some embodiments, V is deuterium. In some embodiments, V is fluoro.
  • R 13 is hydrogen. In some embodiments, R 13 is -CH2-OR 14 . [0121] In some embodiments, R 14 is -C(O)-R 15 . In some embodiments, R 14 is -P(O)(OR 16 )2.
  • R 15 is C1-C4 alkyl. In some embodiments, R 15 is C1-C4 alkoxy.
  • n is 0. In some embodiments, n is 1.
  • R 3 and R 4 are independently hydrogen or CH3. In some embodiments, R 3 and R 4 are hydrogen. In some embodiments, R 3 is hydrogen and R 4 is CH3. In some embodiments, R 3 and R 4 are CH3. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form cyclopropyl.
  • p is 1. In some embodiments, p is 0.
  • Y 1 is -O-. In some embodiments, Y 1 is -CH2-.
  • Z is -O-. In some embodiments, Z is -CH2-.
  • Z 1 is -O-
  • R 5 is selected from Cg-Cio aryl; 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms; C3-C6 cycloalkyl ring; and C1-C3 alkyl optionally substituted with C1-C3 alkoxy or phenyl; wherein the Cg-Cio aryl and the 6-membered heteroaryl ring are substituted with 0 to 2 R 6 , and each R 6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyl.
  • R 5 is Cg-Cio aryl, wherein the Cg-Cio aryl is substituted with 0 to 2 R 6 , and each R 6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4
  • R 5 is 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, wherein the 6-membered heteroaryl ring is substituted with 0 to 2 R 6 , and each R 6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyl.
  • R 5 is C3-Cg cycloalkyl ring. In some embodiments, R 5 is [0132] In some embodiments, R 5 is C1-C3 alkyl optionally substituted with C1-C3 alkoxy or phenyl. In some embodiments,
  • -Z’-I is hydrogen
  • Ring D is a Cg-Cio aryl ring. In some embodiments, Ring D is a Cs-Cg cycloalkyl ring. In some embodiments, Ring D is a 4- to 5 -membered heterocycloalkyl ring with 1 ring nitrogen atom. In some embodiments, Ring D is a 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms. In some embodiments, Ring D is a 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms. In some embodiments, Ring D is absent.
  • Ring A is Cg-Cio aryl ring substituted with from 0 to 3 R 7 moieties. In some embodiments, Ring A is C4-Cg cycloalkyl ring substituted with from 0 to 3 R 7 moieties. In some embodiments, Ring A is Cs-Cg cycloalkenyl ring substituted with from 0 to 3 R 7 moieties. In some embodiments, Ring A is 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O, wherein Ring A is substituted with from 0 to 3 R 7 moieties.
  • Ring A is 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, wherein Ring A is substituted with from 0 to 3 R 7 moieties.
  • Ring A is 4- to 11- membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein Ring A is substituted with from 0 to 3 R 7 moieties.
  • Ring A is a 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring
  • Ring B is Cg-Cio aryl, wherein Ring B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n .
  • Ring B is Cs-Cg cycloalkyl ring, wherein Ring B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n .
  • Ring B is Cs-Cg cycloalkenyl ring, wherein Ring B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n .
  • Ring B is 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; wherein Ring B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and - C(O)NR 10 R n .
  • Ring B is 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; wherein Ring B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n .
  • Ring B is 4- to 11-membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein Ring B is substituted with from 0 to 3 R 8 moieties, wherein each R 8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR 10 R n , and -C(O)NR 10 R n .
  • Ring B is absent.
  • a is zero in L which is then represented by formula Ila:
  • a and c are zero in L which is then represented by formula lib: lib where each of b, Ring A, B, and W 1 is as defined herein.
  • a and c are zero and B is absent in L which is then represented by formula lie: where each of b, Ring A, W 1 is as defined herein.
  • b is 1 and W 1 is O or CH2. In some embodiments, L is
  • B is missing, c is zero and W 1 is CH2.
  • b is 0.
  • L is ,
  • R 1 and R 2 are independently selected from hydrogen, Ci-Cg alkyl, L 1 - (C3-C6 cycloalkyl), and L 1 -(4- to 7-membered heterocycloalkyl), wherein said Ci-Cg alkyl, Cs-Cg cycloalkyl and 4- to 7-membered heterocycloalkyl is optionally substituted by one to four R 8 .
  • R 1 and R 2 are independently selected from hydrogen and Ci-Cg alkyl.
  • R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 3- to 11 -membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N, N(R 17 ), and S(O) m as a ring member, wherein said 3- to 11-membered ring is optionally substituted by one to four R 8 .
  • this disclosure provides for a method for modulating or degrading CDK2, which method comprises contacting CDK2 with a compound of formula I’, I, IA, IB, or III, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions wherein CDK2 is modulated or degraded.
  • a method to modulate or degrade CDK2 in a subject comprises administering to said subject an effective amount of a compound of formula I’, I, IA, IB, or III, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
  • a method for treating cancer in a subject in need thereof comprises selecting a subject whose cancer is mediated at least in part by CDK2 and administering to said subject an effective amount of a compound of formula I’, I, IA, IB, or III, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), Emka-Chemce (St. Louis, Missouri, USA).
  • the synthetic realization and optimization of the bifunctional molecules as described herein may be approached in a step-wise or modular fashion.
  • identification of compounds that bind to the target molecules can involve high or medium throughput screening campaigns if no suitable ligands are immediately available. It is not unusual for initial ligands to require iterative design and optimization cycles to improve suboptimal aspects as identified by data from suitable in vitro and pharmacological and/or ADMET assays. Part of the optimization/SAR campaign would be to probe positions of the ligand that are tolerant of substitution and that might be suitable places on which to attach the linker chemistry previously referred to herein. Where crystallographic or NMR structural data are available, these can be used to focus such a synthetic effort.
  • the tert-butyl ester (t-Bu) protecting group is removed under conventional conditions.
  • the t-Bu group is illustrative only and other conventional carboxylic acid blocking groups such as benzyl, methyl, ethyl and the like could be used.
  • a stoichiometric amount of a suitably substituted amine compound, compound 5A in a diluent such as tetrahydrofuran, dioxane, DMF and the like typically in the presence of a suitable base such as diisopropylethylamine, pyridine, triethylamine and the like.
  • a suitable base such as diisopropylethylamine, pyridine, triethylamine and the like.
  • the reaction is typically maintained at from about 20 °C to about 60 °C until it is substantially complete.
  • Conventional workup of the reaction solution can be followed by isolation/purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 6A.
  • the pyrazole nitrogen of compound 6A is protected with ethyl formate group.
  • At least a stoichiometric amount of ethyl carbonochloridate, 7A is combined with compound 6A in an inert diluent such as dichloromethane, dichloroethane, THF, and the like.
  • the reaction is typically maintained at from about 20 °C to about 50 °C until it is substantially complete.
  • Conventional workup of the reaction solution can be followed by isolation/purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 8 A.
  • the ethyl formate group is illustrative only and other conventional amino blocking groups such as benzyl, t-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz) and the like could be used.
  • the benzyloxycarbonyl (Cbz) protecting group is removed by conventional conditions to provide for compound 9A.
  • the Cbz group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxy carbonyl and the like.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 9A.
  • a conventional Buchwald-Hartwig amination reaction wherein at least a stoichiometric equivalent of a mono-protected diamine, compound 11A, is combined with compound 10A, in an inert diluent such as DMF, dioxane, toluene, and the like, typically in the presence of a palladium catalyst (e.g, Pd(dba)2, Pd2(dba)3, PdC12[P(o-tolyl)3]2) and a suitable base such as sodium tert-butoxide, LiHMDS, cesium carbonate, and the like.
  • a palladium catalyst e.g, Pd(dba)2, Pd2(dba)3, PdC12[P(o-tolyl)3]2
  • a suitable base such as sodium tert-butoxide, LiHMDS, cesium carbonate, and the like.
  • the reaction is typically maintained at from 80° to 120°C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 12A.
  • the methyl ester protecting group is removed under conventional basic hydrolytic conditions to provide for compound 13 A.
  • the methyl ester group is illustrative only and other conventional carboxylic acid protecting groups such as benzyl, ethyl, tert-butyl and the like can be used.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 13 A.
  • the t-butoxycarbonyl (t-BOC) protecting group is removed by conventional conditions.
  • the t-BOC group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 17A.
  • the reaction is typically conducted in an inert solvent such as DME, THF, DMF, and the like under a blue LED.
  • the reaction is typically maintained at from 20°C to 60°C until it is substantially complete.
  • Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography, and the like to provide for compound 20A.
  • the trimethylsilylethoxymethy (SEM) and t-butoxycarbonyl (t-BOC) protecting group are removed by conventional conditions.
  • SEM and t-BOC group are illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenyhnethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like could be used.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 21 A.
  • the reaction is typically conducted in an inert solvent such as DME, THF, DMF, and the like under a blue LED.
  • the reaction is typically maintained at from 20°C to 60°C until it is substantially complete.
  • Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography, and the like to provide for compound 23A.
  • the trimethylsilylethoxymethy (SEM) protecting group is removed by conventional conditions.
  • SEM group are illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p- nitrobenzyloxycarbonyl and the like could be used.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 24 A.
  • the reaction is typically conducted at from about 0° to about 30° C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 25A.
  • the ethyl formate and N- protecting groups are removed by conventional conditions, such as basic hydrolytic or acidic conditions to provide for compound 26A.
  • the ethyl formate group is illustrative only and other conventional N-pyrazole protecting groups such as benzyl, tert-butyl and the like can be used.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPEC), and the like to provide for compound 26A.
  • the reaction is typically conducted at from about 0° to about 30° C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 28 A.
  • protecting group strategies and/or functional group interconversions may be required to facilitate the preparation of the desired materials.
  • Such chemical processes are well known to the synthetic organic chemist and many of these may be found in texts such as "Greene's Protective Groups in Organic Synthesis” Peter G. M. Wuts and Theodora W. Greene (Wiley), and “Organic Synthesis: The Disconnection Approach” Stuart Warren and Paul Wyatt (Wiley).
  • reaction in Scheme 8 at least a stoichiometric amount of a suitable amine, compound 26A is combined with compound 24A under conventional reductive amination reaction conditions well known in the art including the use of NaCNBtU. NaBH(OAc)3, NaBH 4 and the like.
  • the reaction is typically conducted in an inert solvent such as MeCN, MeOH, THF, and the like.
  • the reaction is typically conducted at from about 0 °C to about 30 °C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like are optionally used to provide a compound of formula I.
  • reaction in Scheme 9 at least a stoichiometric amount of a suitable amine, compound 28A is combined with compound 21A under conventional reductive amination reaction conditions well known in the art including the use of NaCNBHs. NaBH(OAc)3, NaBPh and the like.
  • the reaction is typically conducted in an inert solvent such as MeCN, MeOH, THF, and the like.
  • the reaction is typically conducted at from about 0 °C to about 30 °C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like are optionally used to provide a compound of formula I.
  • reaction in Scheme 10 at least a stoichiometric amount of a suitable amine, compound 28A is combined with compound 17A under conventional reductive amination reaction conditions well known in the art including the use of NaCNBHs. NaBH(OAc)3, NaBtE and the like.
  • the reaction is typically conducted in an inert solvent such as MeCN, MeOH, THF, and the like.
  • the reaction is typically conducted at from about 0 °C to about 30 °C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography.
  • conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like are optionally used to provide a compound of formula I.
  • the compounds and compositions described herein are useful in methods for treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part, by CDK2.
  • the CDK2 dependent disease or disorder is a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2.
  • the methods comprise administering to a subject suffering from a CDK2 dependent disease or disorder an effective amount of a compound as described herein, e.g., a compound of formula F, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
  • a compound as described herein e.g., a compound of formula F, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
  • a compound as described herein e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient, for use in treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part, by CDK2, or is a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2.
  • CCNE1 cyclin El
  • CCNE2 cyclin E2
  • a compound as described herein e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient for use in treating an CDK2 dependent disease or disorder.
  • a compound as described herein e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, in the preparation of a medicament for treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part, by CDK2, or is a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2.
  • CCNE1 cyclin El
  • CCNE2 cyclin E2
  • the method relates to a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient, for use in manufacture of a medicament for reducing CDK2 protein levels where reduction of such protein levels treats or ameliorates the disease or disorder.
  • a compound as described herein e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient, for use in manufacture of a medicament for reducing CDK2 protein levels where reduction of such protein levels treats or ameliorates the disease or disorder.
  • the methods described herein comprise use of a prodrug of a compound as described herein.
  • the method relates a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient wherein the CDK2 degradation at 1 pM concentration of the compound as described herein is in the range of about 25%-99%.
  • the CDK2 degradation is measured by the assay described in the biological example. In some embodiments, the CDK2 degradation is from about 25% to about 50%, from about 45% to about 70%, from about 65% to about 90% or from about 75% to about 99%.
  • the CDK2 degradation is from about 25% to about 35%, from about 35% to about 45%, from about 45% to about 55%, from about 55% to about 65%, from about 65% to about 75%, from about 75% to about 85%, from about 85% to about 99%. In some embodiments, the CDK2 degradation is more than 60%. In some embodiments, the CDK2 degradation is more than 70%. In some embodiments, the CDK2 degradation is more than 80%. In some embodiments, the CDK2 degradation is more than 90%.
  • CDK2 dependent diseases or disorders such as cancers including, but not limited to, liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein- Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma (e.g., diffuse large B-cell lymphoma).
  • cancers including, but not limited to, liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis,
  • the cancer may be selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma.
  • the CDK2 -dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triplenegative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).
  • NSCLC non-small cell lung cancer
  • TNBC triplenegative breast cancer
  • NPC nasopharyngeal cancer
  • mssCRC microsatellite stable colorectal cancer
  • thymoma thymoma
  • carcinoid gastrointestinal stromal tumor
  • the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple -negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).
  • the CDK2 -dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC).
  • compounds or compositions described herein are active against solid tumors.
  • the compounds of the disclosure can be administered in effective amounts to treat or prevent or reduce the risks of developing a disease or disorder as discussed herein and/or to prevent or reduce the rate of the development or progression thereof in a subject.
  • methods of using the compounds of the present application comprise administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.
  • compounds as described herein are useful in the treatment of proliferative disorders (e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases).
  • proliferative disorders e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases.
  • levels of cell proteins of interest e.g., pathogenic and oncogenic proteins are modulated, or their growth is inhibited or the proteins are degraded by contacting said cells with an compound or composition, as described herein.
  • the compounds are useful in treating cancer.
  • methods for the treatment of cancer comprising administering a therapeutically effective amount of a compound or composition, as described herein, to a subject in need thereof.
  • a method for the treatment of cancer comprising administering a therapeutically effective amount of a compound, or a pharmaceutical composition comprising a compound as described herein to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result.
  • the compounds of present application are administered orally or intravenously.
  • a “therapeutically effective amount” of the compound or pharmaceutical composition is that amount effective for killing or inhibiting the growth of tumor cells.
  • the compounds and compositions, according to the method of the present application may be administered using any amount and any route of administration effective for killing or inhibiting the growth of tumor cells.
  • the expression “amount effective to kill or inhibit the growth of tumor cells,” as used herein, refers to a sufficient amount of agent to kill or inhibit the growth of tumor cells.
  • 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 disease, the particular anticancer agent, its mode of administration, and the like.
  • Another aspect of the application relates to a method of treating or lessening the severity of a disease or condition associated with a proliferation disorder in a patient, said method comprising a step of administering to said patient, a compound described herein (e.g., compound of formula I’, formula I, or formula III) or a composition comprising said compound.
  • a compound described herein e.g., compound of formula I’, formula I, or formula III
  • a composition comprising said compound.
  • the compounds and compositions, according to the method of the present application may be administered using any amount and any route of administration effective for the treatment of cancer and/or disorders associated with cell hyperproliferation.
  • the expression “effective amount” as used herein refers to a sufficient amount of agent to inhibit proliferation, or refers to a sufficient amount to reduce the effects of cancer.
  • 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 diseases, the particular anticancer agent, its mode of administration, and the like.
  • the present application also provides methods of protecting against a proliferative disorder in a subject in need thereof or the treatment of a proliferative disorder in a subject in need thereof by administering a therapeutically effective amount of compound or composition as described herein to a subject in need of such treatment.
  • the proliferative disorder can be cancer or a precancerous condition.
  • the present application also provides the use of compound as described herein for the preparation of a medicament useful for the prevention of a proliferative disorder.
  • proliferative disorder refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous.
  • exemplary proliferative disorders of the application encompass a variety of conditions wherein cell division is deregulated.
  • Exemplary proliferative disorder include, but are not limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells.
  • a proliferative disorder includes a precancer or a precancerous condition.
  • a proliferative disorder includes cancer.
  • the methods provided herein are used to treat or alleviate a symptom of cancer.
  • cancer includes solid tumors, as well as, hematologic tumors and/or malignancies.
  • precancer cell or “precancerous cell” is a cell manifesting a proliferative disorder that is a precancer or a precancerous condition.
  • cancer cell or “cancerous cell” is a cell manifesting a proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers.
  • non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gramnegative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart
  • a “proliferative disorder of the hematologic system” is a proliferative disorder involving cells of the hematologic system.
  • a proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia.
  • a proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system.
  • One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, N.Y.
  • levels of cell proteins of interest e.g., pathogenic and oncogenic proteins are modulated, or their growth is inhibited by contacting said cells with an compound or composition, as described herein.
  • the compounds are useful in treating cancer.
  • the present application provides pharmaceutically acceptable derivatives of the compounds described herein, and methods of treating a subject using such derivative, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents.
  • Other therapies or anticancer agents that may be used in combination with the compounds and compositions disclosed herein including surgery, radiotherapy, endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabine, Gemcitabine), spindle poison
  • a pharmaceutical composition as described herein, comprising a compound as disclosed herein further comprise one or more additional therapeutically active ingredients (e.g., a chemotherapeutic agent and/or a palliative agent).
  • additional therapeutically active ingredients e.g., a chemotherapeutic agent and/or a palliative agent.
  • palliative refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not considered to be curative.
  • palliative treatments encompass painkillers, antinausea medications and anti-sickness drugs.
  • chemotherapy, radiotherapy and surgery can all be used palliatively (that is, to reduce symptoms without going for cure; e.g., for shrinking tumors and reducing pressure, bleeding, pain and other symptoms of cancer).
  • Administration of the disclosed compounds and pharmaceutical compositions can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
  • compositions comprising a compound of Formula I’, Formula I, or Formula III, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may further include an excipient, diluent, or surfactant.
  • compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, timerelease capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, timerelease capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
  • compositions for oral administration include tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and/or polyethylene glycol, stearic acid,
  • Illustrative liquid pharmaceutical compositions such as injectable compositions can, for example, be prepared by dissolution, dispersion, etc.
  • a compound as described herein can be dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
  • Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectable s can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • the disclosed compounds can be formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • the disclosed compounds can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a fdm of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564, which is hereby incorporated by reference in its entirety.
  • Disclosed compounds can be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled.
  • the disclosed compounds can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, poly orthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a polymer e.g., a poly carboxy lie acid polymer, or a polyacrylate.
  • the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present disclosure.
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the disclosure may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the disclosure typically comprises directions for administration.
  • compositions of this disclosure can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
  • compositions are comprised of, in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are nontoxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this disclosure in an aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • compositions of this disclosure may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient.
  • a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising a compound of this disclosure that can be formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below. Formulation Examples
  • Ingredient capsule mg compound of this disclosure 200 lactose, spray-dried 148 magnesium stearate 2
  • Ingredient Amount compound of this disclosure 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.0 g sorbitol (70% solution) 13.00 g
  • a suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
  • the dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed.
  • a physician or veterinarian can determine and prescribe an effective amount of a compound as described herein to treat or prevent the disease or disorder presented.
  • Effective dosage amounts of the disclosed compounds when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition.
  • Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses.
  • the compositions are in the form of a tablet that can be scored.
  • the resulting solution was stirred for 12 hours at 50°C.
  • the mixture was quenched with water (0.1 mL).
  • the mixture was purified by pre-HPLC [Phenomenex Luna Cis 100 mm x 40 mm x 3 pm; 25 to 55% 1% formic acid in water in ACN] and lyophilized to give 2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)piperazin-l-yl)methyl)phenyl)acetic acid.
  • reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give tert-butyl 2-(4-(4-(2- (2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine-l-carbonyl)phenyl)acetate which was used in next step directly without purification.
  • reaction was purified by prep-HPLC (column: Welch Xtimate Cis 180 mm x 70 mm x 10 pm; mobile phase: [H2O (+0.01%TFA)-ACN]; gradient: 35 %-65% B over 20.0 min) and lyophilized to give 4-( 1 -(2-(2,6-dioxopiperidin-3-yl)- 1 ,3 -dioxoisoindolin-5 -yl)piperidin-4-yl)-3 -fluorobenzoic acid.
  • the compounds disclosed herein preferably contain (lR,3S)-cyclopentyl or (lR,3S)-cyclopentyl; such preferred compounds would exclude compounds in Table 1 lacking (1R,3S)- cyclopentyl or (lR,3S)-cyclopentyl.
  • HEK-293T cells were harvested ca. 75% confluent with trypsin and plated (500,000 cells/well) in a 6-well tissue culture plate in 2 m of Dulbecco’s Modified Eagle Medium (DMEM) + 10% Fetal Bovine Serum (FBS) and incubated overnight at 37 °C.
  • DMEM Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • the NanoLuc-CRBN fusion vector contains the coding region of human E3 ligase component cereblon (CRBN) fused to the C-terminus of the NanoLuc luciferase coding region.
  • CRBN human E3 ligase component cereblon
  • a mixture of 10 ng Nluc-CRBN and 990 ng DDB1 Expression Vector was added to 125 pL Opti-Minimum Essential Medium (Opti-MEMTM; Thermo Fisher) along with 2 pL P3000 reagent (Thermo Fisher) in a 1.5 mb epppendorf tube.
  • This solution was added to Lipofectamine 3000 transfection reagent (5 pL; Thermo Fisher) in Opti-MEM (125 pL), mixed well, and incubated for 15 minutes at room temperature. The transfection mixture was added dropwise to cells and incubated overnight at 37 °C, 5% CO2. Following transfection, cells were washed once with PBS, and trypsin (250 pL) was added and incubated 30-45 sec to dislodge cells. Complete media (2 mL) was added to resuspend cells to form a single cell suspension.
  • Opti-MEM 3 mL; wash step repeated x2). After final resuspension in 5 mL Opti-MEM, cells were counted and resuspended at 200,000 cells/mL in Opti-MEM.
  • Cereblon target engagement was monitored by Bioluminescence Resonance Energy Transfer (BRET) in transfected HEK-293T cells using the NanoBRET TE Intracellular E3 Ligase Assay (Promega). Briefly, 384-well plates (white opaque plates, Coming 3574, low binding surface) were seeded with transfected HEK-293T cells (38 pL/well). 2 pL of 10 pM CRBN tracer (diluted 1:5 in Tracer Dilution Buffer) was added to each well. Plates were centrifuged at 320x g for 1 min at room temperature.
  • BRET Bioluminescence Resonance Energy Transfer
  • Test compounds were added in a 11 -point dilution series (typically 10 pM to 100 pM) using a TECAN D300e Digital Dispenser. Plates were shaken for 2 minutes on a microplate shaker to mix compounds. Plates were centrifuged at 320x g for 1 min at room temperature, and subsequently incubated for 2 hours at 37 °C.
  • HiBiT- CDK2 HEK293T cells were harvested ca. 75% confluent with trypsin and plated (500,000 cells/well) in a 6-well tissue culture plate in 2 mL of Dulbecco’s Modified Eagle Medium (DMEM) + 10% Fetal Bovine Serum (FBS) and incubated overnight at 37 °C.
  • DMEM Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • CDK2 degradation assays were carried out by harvesting the HiBiT- CDK2 HEK293T reporter ceil lines and resuspending the cells in media formulated for reduced background fluorescence.
  • the respective cell lines were seeded at a density of 4,000 cells/well into 384 well white opaque TC plates (Greiner 781080-20). The cells were incubated overnight to allow for attachment to the assayplate (37°C with humidified air and 5% CO2 for all incubations). Dilutions of the compounds were prepared in dimethyl sulfoxide (DMSO) from 10 mM compound stock solutions in DMSO.
  • DMSO dimethyl sulfoxide
  • the assayplates were treated with appropriate concentrations of the compounds by dispensing the DMSO dilutions in quadruplicate wells with an upper limit of 0.5% final DMSO. After a 6-hour incubation with the compounds.
  • HiBiT lytic buffer, 1: 100 LgBiT and 1:50 HiBiT were added at 30pl/welI, and plates were incubated at room temperature for 2 hours covered with foil. Images were acquired using the ClarioStar plate reader system (cells maintained at 37 °C during imaging). Cell Reporter Xpress software was utilized to segment cells and determine fluorescence intensities, which were used to construct dose-response curves and calculation of degradation DC50S (GraphPad Prism). The percent degradation amounts were calculated visually from the curves generated at a concentration of 1 and 10 micromolar.
  • HEK-293T cells were harvested ca. 75% confluent with trypsin and plated (500,000 cells/well) in a 6-well tissue culture plate in 2 mL of Dulbecco’s Modified Eagle Medium (DMEM) + 10% Fetal Bovine Serum (FBS) and incubated overnight at 37 °C.
  • DMEM Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • CDK2 target engagement was monitored by Bioluminescence Resonance Energy Transfer (BRET) in transfected HEK-293T cells using the NanoBRET Assay. Briefly, 384-well plates (white opaque plates, Coming 3574, low binding surface) were seeded with transfected HEK-293T cells (38 pL/well). 2 pL of 10 pM K-10 tracer (diluted 1:5 in Tracer Dilution Buffer) was added to each well. Plates were centrifuged at 320x g for 1 min at room temperature. Test compounds were added in a 10- point dilution series (typically 10 pMto 100 pM) using a TECAN D300e Digital Dispenser. Plates were shaken for 20 secondss on a microplate shaker to mix compounds. Plates were centrifuged at 320x g for 1 min at room temperature, and subsequently incubated for 2 hours at 37 °C.
  • BRET Bioluminescence Resonance Energy Transfer
  • Table 5 and Table 6 show results from the assays described above.

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Abstract

This disclosure provides compounds and pharmaceutically acceptable salts thereof that are useful as modulators of targeted ubiquitination. The compounds disclosed herein bind to and degrade one or more cyclin dependent kinases 2 (CDK2).

Description

COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THAT DEGRADE CDK2
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Provisional Application 63/349,523, filed June 6, 2022, the contents of which are incorporated by reference herein in their entirety.
FIELD
[0002] This disclosure provides compounds and pharmaceutically acceptable salts thereof that are useful as modulators of targeted ubiquitination. The compounds disclosed herein bind to and/or degrade one or more cyclin dependent kinases (CDKs) and, accordingly, are useful in treating abnormal cell growth such as cancer. Also disclosed are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts thereof, and methods of using such compounds and their salts in the treatment of various CDK-mediated diseases or disorders.
STATE OF THE ART
[0003] Cyclin-Dependent Kinases and related serine/threonine protein kinases are important cellular enzymes that perform essential features in regulating cell division and proliferation. CDKs 1-4, 6, 10, and 11 have been reported to play a direct role in cell cycle progression whereas CDKs 3,5, and 7-9 may play an indirect role (e.g., through activation of other CDKs, regulation of transcription or neuronal functions).
[0004] Overexpression of CDK2 is associated with abnormal regulation of the cell -cycle. Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed in cancer. Such overexpression has been associated with poor outcomes in breast cancer including triple negative breast cancer.
[0005] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.
[0006] There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See e.g., Li et al. “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling.” PLOS One 2008, (3) 1487; Bemdsen et al. “New insights into ubiquitin E3 ligase mechanism” Nat. Struct. Mol. Biol. 2014, 21:301; Deshaies et al. “RING domain E3 ubiquitin ligases” Ann. Rev. Biochem. 2009, 78:399; Sprattetal. “RBRE3 ubiquitin ligases: new structures, new insights, new questions” Biochem. 2014, 458:421; and Wang et al., “Roles of F-box proteins in cancer” Nat. Rev. Cancer. 2014, 14:233. [0007] UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair, and biogenesis of organelles.
[0008] Aberrations in the process have recently been implicated in the pathogenesis of several diseases, both inherited and acquired. These diseases fall in to two major groups: (a) those that result from loss of function with the resultant stabilization of certain proteins, and (b) those that result from gain of function, i.e. abnormal or accelerated degradation of the protein target.
[0009] The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome- dependent degradation. Compounds that act as molecular glues can induce or stabilize protein-protein interactions between a target protein and an E3 ubiquitin ligase ligand, leading to protein ubiquitination and subsequent proteasome-mediated degradation via the recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins. See e.g., Crews, Chem. & Biol. 2010, 17 (6): 551; Schneekloth and Crews, Chem Bio Chem., 2005, 6 (1): 40.
[0010] There is an ongoing need for effective treatments for diseases such as hyperplasias and cancers. However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents. As such, small molecule therapeutic agents that leverage E3 ligase mediated protein degradation to target cancer-associated proteins, such as CDK, including CDK2, hold promise as therapeutic agents. Accordingly, there remains a need for compounds that target CDKs, especially CDK2, for degradation which compounds would be useful as therapeutic agents.
SUMMARY
[0011] Disclosed are compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising said compounds or pharmaceutically acceptable salts thereof, and methods for use of said compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which bind to and/or degrade one or more cyclin dependent kinases (CDKs). An advantage of the compounds provided herein is that a broad range of pharmacological activities are possible, consistent with the degradation/inhibition of CDKs and modulation of targeted ubiquitination. In addition, the disclosure provides methods of using the compounds described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., breast cancer, in a subject in need thereof.
[0012] In some embodiments, the disclosed compounds are represented by formula I’:
Figure imgf000004_0001
r or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein
Y is N or C-V;
Ring C is
Figure imgf000004_0002
wherein the solid bond 1 attaches Ring C to Y and the solid bond 2 attaches Ring C to L;
V is selected from hydrogen, deuterium, and fluoro;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
R12 and R12 are independently selected from hydrogen, deuterium, and fluoro; or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R3 and R4 are independently hydrogen or CH3; or R3 and R4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R13 is hydrogen or -CH2-OR14;
R14 is -C(O)-R15 or -P(O)(OR16)2;
R15 is C1-C4 alkyl or C1-C4 alkoxy; each R16 is independently hydrogen or C1-C4 alkyl; Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
Y1 is -O- or -CH2-;
Z is -O- or -CH2-;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, I -(C3-Cg cycloalkyl), and L1-(4- to 7-membered heterocycloalkyl), wherein said Ci-Cg alkyl, G-Cg cycloalkyl and 4- to 7- membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 11- membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N, N(R17), and S(O)m as a ring member, wherein said 3- to 11-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, C1-C4 alkyl, or C(O)-(Ci-C4 alkyl);
R18 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C(O)-(Ci-C4 alkyl); m is 0, 1 or 2;
L1 is a bond or a C1-C2 alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000005_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein Ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein Ring B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or Ring B is absent; a, b, and c are independently 0 or 1 ; each of W and W2, if present, is independently Ci-Ce alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Ce alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W, W1 and W2 is no more than 6; or when each of W and W2 are absent, then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms; and
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
[0013] In some embodiments, the disclosed compounds are represented by formula I:
Figure imgf000006_0001
I or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein
Ring C is
Figure imgf000006_0002
wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
V is selected from hydrogen, deuterium, and fluoro;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
R12 and R12 are independently selected from hydrogen, deuterium, and fluoro; or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R13 is hydrogen or -CH2-OR14;
R14 is C(O)-R15 or -P(O)(OR16)2;
R15 is C1-C4 alkyl or C1-C4 alkoxy; each R16 is independently hydrogen or C1-C4 alkyl; Ring D is selected from G-Go aryl ring, C5-G cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, L’-G-G, cycloalkyl, and L1-4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, -G, cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 4- to 6- membered ring optionally containing an additional heteroatom selected from O, N, N(R17), and S(O)m as a ring member, wherein said 4- to 6-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, Ci-G alkyl, or C(O)-Ci-C4 alkyl;
R18 is hydrogen, Ci-G alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
L1 is a bond or a G-G alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000007_0001
wherein:
Ring A is selected from Cg-Go aryl ring; G-G cycloalkyl ring; G-G cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, G-G alkyl, G-G fluoroalkyl, G-G alkoxy, G-G fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or G-G alkyl;
Ring B is selected from G-Go aryl; G-G cycloalkyl ring; G-G cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, G-G alkyl, G-G fluoroalkyl, G-G alkoxy, G-G fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; a, b, and c are independently 0 or 1 ; each of W and W2, if present, is independently G-G alkylene optionally substituted with 1 to 3 R9 and W1, if present, is O, S, NR18 or G-G alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W, W1 and W2 is no more than 6; or when each of W and W2 are absent, then W1 further comprises G-G heteroalkylene containing 1 to 3 oxygen atoms; and R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
[0014] In some embodiments, the disclosed compounds are represented by formula IA:
Figure imgf000008_0001
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Ring
Figure imgf000008_0002
wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
V is hydrogen;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
R12 and R12 are hydrogen, or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R13 is hydrogen;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4 to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 5-10 membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
Z is -O- or -CH2-;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, L1-(C3-Cg cycloalkyl), and L1-(4- to 7-membered heterocycloalkyl), wherein said Ci-Cg alkyl, C’s-Cg cycloalkyl and 4- to 7- membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 11- membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N(R17), and S(O)m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R8; R17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl;
R18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
L1 is a bond or a C1-C2 alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000009_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to
10-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to
11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; b and c are independently 0 or 1 ;
W2, if present, is Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W1 and W2 is no more than 4; and
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy; or when W is absent then W1 is C4-C8 heteroalkylene containing 1 to 3 oxygen atoms.
[0015] In some embodiments, the disclosed compounds are represented by formula IB:
Figure imgf000010_0001
IB or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Ring
Figure imgf000010_0002
wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
V is hydrogen;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
R12 and R12 are hydrogen, or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R13 is hydrogen;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 5-10 membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
Z is -O- or -CH2-;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, L'-G-Cg cycloalkyl, and L1-4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, C -Cg cycloalkyl and 4- to 7-membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 11- membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N(R17), and S(O)m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl;
R18 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
L1 is a bond or a C1-C2 alkylene optionally substituted with one to four R9; L is represented by the formula:
Figure imgf000011_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to
10-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to
11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; b and c are independently 0 or 1 ;
W2, if present, is Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W1 and W2 is no more than 4;
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy; and when W2 is absent then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms.
[0016] In some embodiments, the disclosed compounds are represented by formula III:
Figure imgf000011_0002
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein
Y is N or C-V;
Ring C is
Figure imgf000012_0001
wherein the solid bond 1 attaches Ring C to Y and the solid bond 2 attaches Ring C to L;
V is selected from hydrogen, deuterium, and fluoro;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and Cwfluoroalkyloxy;
R12 and R12 are independently selected from hydrogen, deuterium, and fluoro; or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R3 and R4 are independently hydrogen, halo, or CH3; or R3 and R4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
Y1 is -O- or -CH2-;
Z1 is -O-, and R5 is selected from Cg-Cio aryl; 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms; C3-C6 cycloalkyl ring; and C1-C3 alkyl optionally substituted with C1-C3 alkoxy or phenyl; wherein the Cg-Cio aryl and the 6-membered heteroaryl ring are substituted with 0 to 2 R6, and each R6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyl; or -Z’-IV is hydrogen;
R13 is hydrogen or -CH2-OR14;
R14 is C(O)-R15 or -P(O)(OR16)2;
R15 is C1-C4 alkyl or C1-C4 alkoxy; each R16 is independently hydrogen or C1-C4 alkyl;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
R18 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C(O)-Ci-C4 alkyl;
L is represented by the formula:
Figure imgf000012_0002
wherein: Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; a, b, and c are independently 0 or 1 ; each of W and W2, if present, is independently Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W, W1 and W2 is no more than 6; or when each of W and W2 are absent, then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms; and
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
Figure imgf000013_0001
Figure imgf000013_0002
some embodiments, X is hydrogen or halo. In some embodiments, X is fluoro. [0018] In some embodiments, Ring D is a Cg-Cio aryl ring. In some embodiments, Ring D is a Cs-Cg cycloalkyl ring. In some embodiments, Ring D is a 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms. In some embodiments, Ring D is a 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms. In some embodiments, Ring D is absent. In some embodiments, Ring D is absent,
Figure imgf000014_0001
[0019] In some embodiments, Ring A is a 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring
Figure imgf000014_0002
[0020] In some embodiments, a is zero in L, and the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is represented by formula Ila:
Figure imgf000014_0003
[0021] In some embodiments, a and c are zero in L, and the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is represented by formula lib:
Figure imgf000014_0004
[0022] In some embodiments, B is a 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, -NR10Rn, and -C(O)NR10Rn
Figure imgf000015_0001
Figure imgf000015_0002
[0026] In some embodiments, L is
Figure imgf000016_0001
[0027] In some embodiments, a and c are zero and B is absent in L, and the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is represented by formula lie:
Figure imgf000016_0002
[0028] In some embodiments, b is 1 and W1 is O or CH2. In some embodiments, L is
Figure imgf000016_0003
Figure imgf000016_0004
[0029] In some embodiments, b is 0. In some embodiments, L is
Figure imgf000016_0005
Figure imgf000016_0006
[0030] In some embodiments, b is 1 and W1 is -CH2-. In some embodiments, L is
Figure imgf000016_0007
Figure imgf000016_0008
[0031] In some embodiments, b is 0. In some embodiments, L is
Figure imgf000016_0009
.
[0032] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, p is 1.
[0033] In some embodiments, R1 and R2 are independently selected from hydrogen and Ci-Cg alkyl.
In some embodiments, R1 and R2 taken together with the nitrogen atom to which they are attached form a 3 - to 11 -membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N, N(R17), and S(O)m as a ring member, wherein said 4- to 6-membered ring is optionally
Figure imgf000017_0004
[0034] In some embodiments, Z is -O-. In some embodiments, Z is -CH2-. In some embodiments, Y is C-V. In some embodiments, V is hydrogen. In some embodiments, Y is N. In some embodiments, Y1 is -CH2-.
[0035] In some embodiments, R5 is Cg-Cw aryl substituted with 0 to 2 R6. In some embodiments, R5 is
Figure imgf000017_0001
Figure imgf000017_0002
C3-C6 cycloalkyl ring. In some embodiments, R5 is
Figure imgf000017_0003
. In some embodiments, -Z’-R2 is hydrogen.
[0036] In some embodiments, the compound is selected from Table 1 or Table 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
[0037] In some embodiments, the compounds as described herein modulate CDK2. In some embodiments, the compounds as described herein bind to CDK2. In some embodiments, the compounds as described herein degrade CDK2. [0038] In some embodiments, this disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound, such as an amount effective for modulating or degrading CDK2.
[0039] In some embodiments, this disclosure provides a method for modulating or degrading CDK2, which method comprises contacting CDK2 with a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions wherein CDK2 is bound to said compound and modulated or degraded.
[0040] In some embodiments, this disclosure provides a method for modulating or degrading CDK2 in a subject, which method comprises administering to said subject a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient, under conditions wherein said CDK2 is bound to said compound and modulated or degraded.
[0041] In some embodiments, this disclosure provides a method for treating a CDK2 dependent disease or disorder, or a disease or disorder that is mediated, at least in part by, CDK2, or a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2, in a subject in need thereof, which method comprises administering to said subject an effective amount of a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
[0042] In some embodiments, this disclosure provides a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, for use in treating a CDK2 dependent disease or disorder, or a disease or disorder that is mediated, at least in part by, CDK2, or is a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2.
[0043] In some embodiments, this disclosure provides a use of a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, in the preparation of a medicament for treating a CDK2 dependent disease or disorder, or a disease or disorder that is mediated, at least in part by, CDK2, or is a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2. [0044] In some embodiments, the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2 is one or more selected from liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein- Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma. In some embodiments, the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2 is selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma. In some embodiments, the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2 is selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus. [0045] In some embodiments, this disclosure provides a method for treating hyperplasias in a subject in need thereof which method comprises administering to said subject an effective amount of a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient. [0046] In some embodiments, this disclosure provides a method for treating cancer in a subject in need thereof which method comprises administering to said subject an effective amount of a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
[0047] In one embodiment, the cancer treated in the methods described herein is breast cancer, such as triple negative breast cancer.
[0048] In some embodiments, the methods disclosed herein further comprise administering to the subject one or more additional therapies or therapeutic agents. In some embodiments, the one or more additional therapies or therapeutic agents are one or more selected from surgery, radiotherapy, endocrine therapy, biologic response modifiers, hyperthermia and cryotherapy, agents to attenuate any adverse effects, alkylating drugs, antimetabolites, purine antagonists and pyrimidine antagonists, spindle poisons, podophyllotoxins, antibiotics, nitrosoureas, inorganic ions, enzymes, and hormones.
DETAILED DESCRIPTION
[0049] This disclosure provides compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions to treat diseases, disorders, or conditions mediated, at least in part, by CDK2.. However, prior to providing a detailed description of the disclosure, the following terms will first be defined. If not defined, terms used herein have their generally accepted scientific meaning.
[0050] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. As used herein, a phrase in the form “A/B” or in the form “A and/or B” means (A), (B), or (A and B); a phrase in the form “at least one of A, B, and C” means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).
[0051] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.
[0052] The prefix “Cu-V” indicates that the following group has from u to v carbon atoms. For example, “Ci-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.
[0053] The term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximation which may vary depending on the context as will be understood by those skilled in the art. In cases where further definition of “about” is required and not otherwise specified, the term “about” means that the value so modified may vary by +/- 10%. [0054] “Comprising” or “comprises” means that the compositions and methods so modified include at least the recited elements.
[0055] “Consisting essentially of’ when used to define compositions and methods means that the compositions and methods so modified include at least the recited elements and do not include other materials or steps that would materially affect the basic and novel characteristic(s) of the claimed disclosure. Thus, a composition or method “consisting essentially of’ recited elements could include other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure.
[0056] “Consisting of’ when used to define compositions and methods means that the compositions and methods so modified include the recited elements and do not include more than trace amounts of other ingredients or do not include other substantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure.
[0057] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3 -hexyl, and 3 -methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CFE CFfi), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., - CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CFE CFfi) and isopropyl (i.e., -CH( CThfi).
[0058] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group (for example, methylenyl, ethylenyl, and propylenyl), an “arylene” group or an “arylenyl” group (for example, phenylenyl or napthylenyl, or quinolinyl for heteroarylene), respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
[0059] “Alkenyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 12 carbon atoms (i.e., C2-12 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3 -butadienyl).
[0060] “Alkynyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 12 carbon atoms (i.e., C2-12 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.
[0061] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1 ,2-dimethylbutoxy .
[0062] “Alkylthio” refers to the group “alkyl-S-”. “Alkylsulfmyl” refers to the group “alkyl-S(O)-”. “Alkylsulfonyl” refers to the group “alkyl-S(O)2-”. “Alkylsulfonylalkyl” refers to -alkyl-S(O)2-alkyl.
[0063] “Acyl” refers to a group -C(O)Ry, wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein. Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.
[0064] “Amido” refers to both a “C-amido” group which refers to the group -C(0)NRyRz and an “N- amido” group which refers to the group -NRyC(0)Rz, wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein, or Ry and Rz are taken together to form a cycloalkyl or heterocyclyl; each of which may be unsubstituted or substituted, as defined herein.
[0065] “Amino” refers to the group -NRyRz wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
[0066] “Amidino” refers to -C(NRy)(NRz2), wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
[0067] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., Cg-20 aryl), 6 to 12 carbon ring atoms (i.e., Cg-i2 aryl), or 6 to 10 carbon ring atoms (i.e., Cg-io aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of point of attachment. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkyl regardless of point of attachment.
[0068] “Carbamoyl” refers to both an “0-carbamoyl” group which refers to the group -0-C(0)NRyRz and an “N-carbamoyl” group which refers to the group -NRyC(0)0Rz, wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein. [0069] “Carboxyl ester” or “ester” refer to both -0C(0)Rx and -C(0)0Rx, wherein Rx is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
[0070] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-14 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5 ]undecanyl .
[0071] “Imino” refers to a group -C(NRy)Rz, wherein Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
[0072] “Imido” refers to a group -C(O)NRyC(O)Rz, wherein Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
[0073] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.
[0074] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3 -bromo-2 -fluoropropyl, 1,2-dibromoethyl, and the like.
[0075] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.
[0076] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group. [0077] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom(s), are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH2OCH3, - CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc ), thioethers (e.g., -CH2SCH3, - CH(CH3)SCH3, -CH2CH2SCH3,-CH2CH2SCH2CH2SCH3, etc ), sulfones (e.g, -CH2S(O)2CH3, - CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc ), and amines (e.g., - CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRyCH2CH2NRyCH3, etc., where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein). As used herein, heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
[0078] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused- heteroaryl rings include, but are not limited to, benzo [d]thiazolyl, quinolinyl, isoquinolinyl, benzo [b]thiophenyl, indazolyl, benzo [d] imidazolyl, pyrazolo[l,5-a]pyridinyl, and imidazo[l,5- a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.
[0079] “Heterocyclyl” - used interchangeably with “heterocycloalkyl”- refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=0) or N-oxide (-0 ) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.4]octanyl, and 6-oxa-l-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3- c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system. In some embodiments, the heterocycloalkyl may be substituted with oxo group(s) on a heteroatom (e.g., S=O, S(=O)2). [0080] ‘ ‘Oxime” refers to the group -CRy(=NOH) wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
[0081] ‘ ‘Oxo” refers to the moiety =0.
[0082] “Sulfonyl” refers to the group -S(O)2Ry, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
[0083] “Sulfinyl” refers to the group -S(O)Ry, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.
[0084] “Sulfonamide” refers to the groups -SC>2NRyRz and -NRySC>2Rz, where Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.
[0085] The terms “optional” or “optionally” means that the subsequently described feature, event or circumstance may or may not be present or occur and that the description includes instances where said feature, event or circumstance is present/occurs and instances in which it does not. Also, the term “unsubstituted or substituted” refers to any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.
[0086] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(Ry)3, wherein each Ry is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.
[0087] In certain embodiments, “substituted” includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRgRh, -NRgC(0)Rh,
Figure imgf000026_0001
“substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -CH2SO2Rg, or -CH2SO2NRgRh In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of Rg and Rh are taken together with the atoms to which they are attached to form a heterocyclyl ring unsubstituted or substituted with oxo, halo, or alkyl unsubstituted or substituted with oxo, halo, amino, hydroxy, or alkoxy.
[0088] Polymers or similar structures of indefinite size arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein.
[0089] Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds (i.e., the amount of labeled forms is above the natural abundance for that form). These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, nC, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36C1, 123I, and 125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H and 14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
[0090] The term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
[0091] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and/or an improvement in therapeutic index. An 18F, 3H, or nC labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.
[0092] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.
[0093] In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino, and/or carboxyl groups, or groups similar thereto.
[0094] Also provided are pharmaceutically acceptable salts, solvates, stereoisomers, and tautomers of the compounds described herein. Unless the context dictates otherwise, reference to a “compound” as described herein includes reference to its pharmaceutically acceptable salts, solvates, stereoisomers, and tautomers. Also provided are isotopically enriched analogs, deuterated analogs, mixtures of stereoisomers, and prodrugs of the compounds described herein.
[0095] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing or suitable for use in a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
[0096] The term “pharmaceutically acceptable salt” of a given compound refers to salts that exhibit the intended efficacy of the reference compound and which are not biologically or otherwise undesirable, e.g., due to toxicity or other properties. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkyl amines (i.e., NfLfalkyl)). dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NfLfsubstitiitcd alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkylfi). alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl^), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl^, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
[0097] Some of the compounds described herein exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
[0098] The compounds described herein, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S')- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms, and various combinations thereof. Optically active (+) and (-), (R)- and (.S)-. or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and/or fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
[0099] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable . The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are non-superimposeable mirror images of one another.
[0100] ‘ ‘Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
[0101] Relative centers of the compounds as depicted herein are indicated graphically using the “thick bond” style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).
[0102] “Prodrug” means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.
[0103] “Subject” refers to a mammal. The mammal can be a human or non-human mammalian organism. A “patient” refers to a human subject.
[0104] “Treating” or “treatment” of a disease or disorder in a subject refers to inhibiting the disease or disorder or arresting its development or ameliorating or causing regression of the disease or disorder. [0105] Unless otherwise specified, “effective amount” refers to an amount of a compound described herein that is sufficient to achieve the intended effect, such as modulating CDK2 or treating a disease or disorder afflicting a subject.
[0106] “Administration” refers to any art recognized form of administration to a subject including injection (e.g., intravenous, subcutaneous, intramuscular), oral (including oral gavage), pulmonary, transdermal, sublingual, transmucosal (e.g., vaginal, nasal, etc.), and the like.
[0107] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, an E3 ubiquitin ligase protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein, and subsequently targets the specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins. In general, the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added by the ubiquitin ligase to a substrate molecule. Mono- ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin. Further complicating matters, different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.
COMPOUNDS
[0108] In one embodiment, this disclosure provides a compound of formula F:
Figure imgf000031_0001
r or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Y is N or C-V;
Ring C is
Figure imgf000032_0001
wherein the solid bond 1 attaches Ring C to Y and the solid bond 2 attaches Ring C to L;
V is selected from hydrogen, deuterium, and fluoro;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
R12 and R12 are independently selected from hydrogen, deuterium and fluoro; or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R3 and R4 are independently hydrogen or CH3; or R3 and R4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R13 is hydrogen or -CH2-OR14;
R14 is -C(O)-R15 or -P(O)(OR16)2;
R15 is C1-C4 alkyl or C1-C4 alkoxy; each R16 is independently hydrogen or C1-C4 alkyl;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
Y1 is -O- or -CH2-;
Z is -O- or -CH2-;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, L1-(G-Cg cycloalkyl), and L1-(4- to 7-membered heterocycloalkyl), wherein said Ci-Cg alkyl, G-Cg cycloalkyl and 4- to 7- membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 11- membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N, N(R17), and S(O)m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, C1-C4 alkyl, or C(0)-(G-C4 alkyl);
R18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
L1 is a bond or a G-C2 alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000033_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; a, b, and c are independently 0 or 1 ; each of W and W2, if present, is independently Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W, W1 and W2 is no more than 6; or when each of W and W2 are absent, then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms; and
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
[0109] In one embodiment, this disclosure provides a compound of formula I:
Figure imgf000033_0002
I or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Ring C is
Figure imgf000034_0001
wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
V is selected from hydrogen, deuterium, and fluoro;
X is selected from hydrogen, halo, hydroxy, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, and C1-4 fluoroalkyloxy;
R12 and R12 are independently selected from hydrogen, deuterium and fluoro or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R13 is hydrogen or -CH2-OR14;
R14 is -C(O)-R15 or -P(O)(OR16)2;
R15 C1-C4 alkyl or C1-C4 alkoxy; each R16 is independently hydrogen or C1-C4 alkyl;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4 to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, L'-C’s-Cg cycloalkyl, and I -4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, C -Cg cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 4- to 6-membered ring optionally containing an additional heteroatom selected from O, N, N(R17), and S(O)m as a ring member, wherein said 4- to 6-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl;
R18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
L1 is a bond or a C1-C2 alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000034_0002
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-4 alkyl, Ci-4fluoroalkyl, C1-4 alkoxy, C1-4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, C 1-4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; a, b, and c are independently 0 or 1 ; each of W and W2, if present, is independently Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W, W1 and W2 is no more than 6; or when each of W and W2 are absent, then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms; and
R9 is independently selected from halo, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, and C1-4 fluoroalkyloxy.
[0110] In one embodiment, this disclosure provides a compound of formula IA:
Figure imgf000035_0001
IA or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Ring C is
Figure imgf000036_0001
wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
V is hydrogen;
X is selected from hydrogen, halo, hydroxy, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, and C Mfluoroalkyloxy ;
R12 and R12 are hydrogen or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R13 is hydrogen;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4 to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 5-10 membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, L'-C’s-Cg cycloalkyl, and I -4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, C -Cg cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 3 - to 6-membered ring optionally containing an additional heteroatom selected from O, N(R17), and S(O)m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl;
R18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
L1 is a bond or a C1-C2 alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000036_0002
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 10- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, CM alkyl, Ci-4fluoroalkyl, C alkoxy, CM fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11- membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4 to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, CM alkyl, CM fluoroalkyl, CM alkoxy, C 1-4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; b and c are independently 0 or 1 ;
W2, if present, is Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W1 and W2 is no more than 4; and
R9 is independently selected from halo, cyano, CM alkyl, CM fluoroalkyl, CM alkoxy, and CM fluoroalkyloxy or when W is absent then W1 is C4-C8 heteroalkylene containing 1 to 3 oxygen atoms.
[OlH] In one embodiment, there is provided a compound of formula IB:
Figure imgf000037_0001
IB or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Ring C is
Figure imgf000037_0002
wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
V is hydrogen; X is selected from hydrogen, halo, hydroxy, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, and C wfluoroalkyloxy ;
R12 and R12 are hydrogen or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R13 is hydrogen;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4 to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 5-10 membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, L'-C’s-Cg cycloalkyl, and I -4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, C -Cg cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 3 - to 6-membered ring optionally containing an additional heteroatom selected from O, N(R17), and S(O)m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl;
R18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
L1 is a bond or a C1-C2 alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000038_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 10- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-4 alkyl, Ci-4fluoroalkyl, C1-4 alkoxy, C1-4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11- membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4 to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, Ci-4fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; b and c are independently 0 or 1 ;
W2, if present, is Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W1 and W2 is no more than 4;
R9 is independently selected from halo, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, and C1-4 fluoroalkyloxy; and when W2 is absent then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms.
[0112] A compound of formula III:
Figure imgf000039_0001
Ill or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Y is N or C-V;
Ring C is
Figure imgf000039_0002
wherein the solid bond 1 attaches Ring C to Y and the solid bond 2 attaches Ring C to L;
V is selected from hydrogen, deuterium, and fluoro;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and Ci-4fluoroalkyloxy;
R12 and R12 are independently selected from hydrogen, deuterium, and fluoro; or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R3 and R4 are independently hydrogen, halo, or CH3; or R3 and R4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; Y1 is -O- or -CH2-;
Z1 is -O-, and R5 is selected from Cg-Cw aryl; 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms; C3-C6 cycloalkyl ring; and C1-C3 alkyl optionally substituted with C1-C3 alkoxy or phenyl; wherein the Cg-Cw aryl and the 6-membered heteroaryl ring are substituted with 0 to 2 R6, and each R6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyl; or -Z^R5 is hydrogen;
R13 is hydrogen or -CH2-OR14;
R14 is C(O)-R15 or -P(O)(OR16)2;
R15 is C1-C4 alkyl or C1-C4 alkoxy; each R16 is independently hydrogen or C1-C4 alkyl;
R18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
L is represented by the formula:
Figure imgf000040_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
Ring B is selected from Cg-Cw aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; a, b, and c are independently 0 or 1 ; each of W and W2, if present, is independently Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W, W1 and W2 is no more than 6; or when each of W and W2 are absent, then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms; and
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
[0113] In some embodiments, Ring
Figure imgf000041_0001
some embodiments, R12 and R12 are independently selected from hydrogen, deuterium, and fluoro. In some embodiments, R12 and R12 are hydrogen. In some embodiments, R12 and R12 are fluoro. In some embodiments, R12 and R12 are deuterium. In some embodiments, R12 and R12 together are oxo.
Figure imgf000041_0004
[0115] In some embodiments, Ring C is
Figure imgf000041_0002
In some embodimetns, Ring C is
Figure imgf000041_0003
[0116] In some embodiments, X is hydrogen or halo. In some embodiments, X is hydrogen. In some embodiments, X is halo. In some embodiments, X is fluoro or chloro. In some embodiments, X is hydrogen, fluoro, or chloro.
[0117] In some embodiments, X is hydroxy. In some embodiments, X is cyano. In some embodiments, X is C1-C4 alkyl. In some embodiments, X is C1-C4 fluoroalkyl. In some embodiments, X is C1-C4 alkoxy. In some embodiments, X is C1-C4 fluoroalkyloxy.
[0118] In some embodiments, Y is C-V. In some embodiments, Y is N.
[0119] In some embodiments, V is hydrogen. In some embodiments, V is deuterium. In some embodiments, V is fluoro.
[0120] In some embodiments, R13 is hydrogen. In some embodiments, R13 is -CH2-OR14. [0121] In some embodiments, R14 is -C(O)-R15. In some embodiments, R14 is -P(O)(OR16)2.
[0122] In some embodiments, R15 is C1-C4 alkyl. In some embodiments, R15 is C1-C4 alkoxy.
[0123] In some embodiments, n is 0. In some embodiments, n is 1.
[0124] In some embodiments, R3 and R4 are independently hydrogen or CH3. In some embodiments, R3 and R4 are hydrogen. In some embodiments, R3 is hydrogen and R4 is CH3. In some embodiments, R3 and R4 are CH3. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form cyclopropyl.
[0125] In some embodiments, p is 1. In some embodiments, p is 0.
[0126] In some embodiments, Y1 is -O-. In some embodiments, Y1 is -CH2-.
[0127] In some embodiments, Z is -O-. In some embodiments, Z is -CH2-.
[0128] In some embodiments, Z1 is -O-, and R5 is selected from Cg-Cio aryl; 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms; C3-C6 cycloalkyl ring; and C1-C3 alkyl optionally substituted with C1-C3 alkoxy or phenyl; wherein the Cg-Cio aryl and the 6-membered heteroaryl ring are substituted with 0 to 2 R6, and each R6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyl.
[0129] In some embodiments, R5 is Cg-Cio aryl, wherein the Cg-Cio aryl is substituted with 0 to 2 R6, and each R6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4
Figure imgf000042_0001
[0130] In some embodiments, R5 is 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, wherein the 6-membered heteroaryl ring is substituted with 0 to 2 R6, and each R6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyl. In some
Figure imgf000042_0002
[0131] In some embodiments, R5 is C3-Cg cycloalkyl ring. In some embodiments, R5 is
Figure imgf000042_0003
[0132] In some embodiments, R5 is C1-C3 alkyl optionally substituted with C1-C3 alkoxy or phenyl. In some embodiments,
Figure imgf000043_0001
[0133] In some embodiments, -Z’-I is hydrogen.
[0134] In some embodiments, Ring D is a Cg-Cio aryl ring. In some embodiments, Ring D is a Cs-Cg cycloalkyl ring. In some embodiments, Ring D is a 4- to 5 -membered heterocycloalkyl ring with 1 ring nitrogen atom. In some embodiments, Ring D is a 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms. In some embodiments, Ring D is a 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms. In some embodiments, Ring D is absent.
Figure imgf000043_0002
[0136] In some embodiments, Ring A is Cg-Cio aryl ring substituted with from 0 to 3 R7 moieties. In some embodiments, Ring A is C4-Cg cycloalkyl ring substituted with from 0 to 3 R7 moieties. In some embodiments, Ring A is Cs-Cg cycloalkenyl ring substituted with from 0 to 3 R7 moieties. In some embodiments, Ring A is 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O, wherein Ring A is substituted with from 0 to 3 R7 moieties. In some embodiments, Ring A is 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, wherein Ring A is substituted with from 0 to 3 R7 moieties. In some embodiments, Ring A is 4- to 11- membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein Ring A is substituted with from 0 to 3 R7 moieties.
[0137] In some embodiments, Ring A is a 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring
Figure imgf000043_0003
[0138] In some embodiments, Ring B is Cg-Cio aryl, wherein Ring B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn. In some embodiments, Ring B is Cs-Cg cycloalkyl ring, wherein Ring B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn. In some embodiments, Ring B is Cs-Cg cycloalkenyl ring, wherein Ring B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn. In some embodiments, Ring B is 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; wherein Ring B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and - C(O)NR10Rn.
[0139] In some embodiments, Ring B is 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; wherein Ring B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn. In some embodiments, Ring B is 4- to 11-membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein Ring B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn. In some embodiments, Ring B is absent.
Figure imgf000044_0001
[0141] In one embodiment, a is zero in L which is then represented by formula Ila:
Figure imgf000045_0001
Ila where each of b, c, Ring A, B, W1, and W2 is as defined herein.
[0142] In one embodiment, a and c are zero in L which is then represented by formula lib:
Figure imgf000045_0002
lib where each of b, Ring A, B, and W1 is as defined herein.
Figure imgf000045_0003
[0144] In one embodiment, a and c are zero and B is absent in L which is then represented by formula lie:
Figure imgf000046_0001
where each of b, Ring A, W1 is as defined herein.
[0145] In some embodiments, b is 1 and W1 is O or CH2. In some embodiments, L is
Figure imgf000046_0002
Figure imgf000046_0003
[0146] In some embodiments, B is missing, c is zero and W1 is CH2.
[0147] In some embodiments, b is 0. In some embodiments, L is
Figure imgf000046_0004
Figure imgf000046_0005
,
[0148] In some embodiments, R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, L1- (C3-C6 cycloalkyl), and L1-(4- to 7-membered heterocycloalkyl), wherein said Ci-Cg alkyl, Cs-Cg cycloalkyl and 4- to 7-membered heterocycloalkyl is optionally substituted by one to four R8. In some embodiments, R1 and R2 are independently selected from hydrogen and Ci-Cg alkyl.
[0149] In some embodiments, R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 11 -membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N, N(R17), and S(O)m as a ring member, wherein said 3- to 11-membered ring is optionally substituted by one to four R8.
Figure imgf000047_0002
. In some embodiments,
Figure imgf000047_0001
[0151] In one embodiment, there is provided a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof:
Table 1
Figure imgf000047_0003
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0002
[0152] In one embodiment, there is provided a compound selected from the compounds of Table 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Table 2
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
[0153] In some embodiments, this disclosure provides for a method for modulating or degrading CDK2, which method comprises contacting CDK2 with a compound of formula I’, I, IA, IB, or III, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions wherein CDK2 is modulated or degraded.
[0154] In some embodiments, there is provided a method to modulate or degrade CDK2 in a subject, which method comprises administering to said subject an effective amount of a compound of formula I’, I, IA, IB, or III, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
[0155] In some embodiments, there is provided a method for treating cancer in a subject in need thereof, which method comprises selecting a subject whose cancer is mediated at least in part by CDK2 and administering to said subject an effective amount of a compound of formula I’, I, IA, IB, or III, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
General Synthetic Methods
[0156] The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[0157] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
[0158] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), Emka-Chemce (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser ’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 2016), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Suppiementals (Elsevier Science Publishers, 2001), Organic Reactions , Volumes 1-40 (John Wiley, and Sons, 2019), March ’s Advanced Organic Chemistry, (John Wiley, and Sons, 8th Edition, 2019), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
Synthesis of Representative Compounds
[0159] The synthetic realization and optimization of the bifunctional molecules as described herein may be approached in a step-wise or modular fashion. For example, identification of compounds that bind to the target molecules (CDK2) can involve high or medium throughput screening campaigns if no suitable ligands are immediately available. It is not unusual for initial ligands to require iterative design and optimization cycles to improve suboptimal aspects as identified by data from suitable in vitro and pharmacological and/or ADMET assays. Part of the optimization/SAR campaign would be to probe positions of the ligand that are tolerant of substitution and that might be suitable places on which to attach the linker chemistry previously referred to herein. Where crystallographic or NMR structural data are available, these can be used to focus such a synthetic effort.
[0160] In a very analogous way one can identify and optimize ligands for an E3 Ligase.
[0161] The general synthesis of the compounds described herein is set forth in the reaction schemes below. In some embodiments, compounds of formula F, formula I, formula III, and sub-formulae thereof are prepared as shown in Schemes 1-10. In the Schemes below, substituents R1, R2, V, Z, n, p, Ring C, Ring D, and L are as defined throughout the specification. Q is a leaving group (including, but not limited to, Br, Cl, I, triflate, and the like) and PG is a protecting group (including, but not limited to, Boc and the like). [0162] Other starting materials used herein are either well known in the art, commercially available, or can be prepared by conventional synthetic methods.
Figure imgf000079_0001
Scheme 1
[0163] In Scheme 1, benzyl (l-(tert-butyl)-3-((lS,37?)-3-hydroxycyclopentyl)-lH-pyrazol-5- yl)carbamate, compound 1A, is disclosed in US2020/247784 which is incorporated herein by reference in its entirety or can be prepared by art recognized procedures.
[0164] As to the reaction in Scheme 1, in the first step at least a stoichiometric equivalent of 4- nitrophenyl carbonochloridate, compound 2 A is combined with compound 1A in a diluent such as tetrahydrofuran, dioxane, DMF and the like, typically in the presence of a suitable base such as pyridine, triethylamine and the like. The reaction is typically maintained at from about 20 °C to about 60 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation/purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 3A.
[0165] In the next step, the tert-butyl ester (t-Bu) protecting group is removed under conventional conditions. The t-Bu group is illustrative only and other conventional carboxylic acid blocking groups such as benzyl, methyl, ethyl and the like could be used.
[0166] In the next step, at least a stoichiometric amount of a suitably substituted amine compound, compound 5A in a diluent such as tetrahydrofuran, dioxane, DMF and the like, typically in the presence of a suitable base such as diisopropylethylamine, pyridine, triethylamine and the like. The reaction is typically maintained at from about 20 °C to about 60 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation/purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 6A.
[0167] In the next step, the pyrazole nitrogen of compound 6A is protected with ethyl formate group. At least a stoichiometric amount of ethyl carbonochloridate, 7A is combined with compound 6A in an inert diluent such as dichloromethane, dichloroethane, THF, and the like. The reaction is typically maintained at from about 20 °C to about 50 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation/purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 8 A. The ethyl formate group is illustrative only and other conventional amino blocking groups such as benzyl, t-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz) and the like could be used.
[0168] In the final step, the benzyloxycarbonyl (Cbz) protecting group is removed by conventional conditions to provide for compound 9A. The Cbz group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxy carbonyl and the like. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 9A.
Figure imgf000080_0001
Scheme 2
[0169] As to the reaction in Scheme 2, in the first step, a conventional Buchwald-Hartwig amination reaction wherein at least a stoichiometric equivalent of a mono-protected diamine, compound 11A, is combined with compound 10A, in an inert diluent such as DMF, dioxane, toluene, and the like, typically in the presence of a palladium catalyst (e.g, Pd(dba)2, Pd2(dba)3, PdC12[P(o-tolyl)3]2) and a suitable base such as sodium tert-butoxide, LiHMDS, cesium carbonate, and the like. The reaction is typically maintained at from 80° to 120°C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 12A.
[0170] In the final step, the methyl ester protecting group is removed under conventional basic hydrolytic conditions to provide for compound 13 A. The methyl ester group is illustrative only and other conventional carboxylic acid protecting groups such as benzyl, ethyl, tert-butyl and the like can be used. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 13 A.
Figure imgf000081_0001
17A
Scheme 3
[0171] As to the reaction in Scheme 3, in the first step, a Ni catalysed photoredox-catalyzed crosscoupling reaction, wherein at least a stoichiometric equivalent of a suitable alkyl halide, compound 15A is combined with 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione, compound 14A, under conventional reaction conditions [Angew. Chem., Int. Ed. 2019, 58, 6152-6163] well known in the art, including the use of (Ir(dF(CF3)ppy)2(dtbbpy))PFg and NiCh as co-catalysts usually in the presence of a base such as sodium carbonate, potassium carbonate and the like. The reaction is typically conducted in an inert solvent such as DME, THF, DMF, and the like under a blue LED. The reaction is typically maintained at from 20°C to 50°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography, and the like to provide for compound 16A.
[0172] In the final step, the t-butoxycarbonyl (t-BOC) protecting group is removed by conventional conditions. The t-BOC group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 17A.
Figure imgf000082_0001
21A
Scheme 4
[0173] As to the reaction in Scheme 4, in the first step, a Ni catalysed photoredox-catalyzed crossCoupling reaction, wherein at least a stoichiometric equivalent of a suitable amine, compound 19A is combined with compound 18A, under conventional reaction conditions [Angew. Chem., Int. Ed. 2019, 58, 6152-6163] well known in the art, including the use of (Ir(dF(CF3)ppy)2(dtbbpy))PFg and NiBr2 as co-catalysts usually in the presence of a base such as sodium carbonate, potassium carbonate, DABCO and the like. The reaction is typically conducted in an inert solvent such as DME, THF, DMF, and the like under a blue LED. The reaction is typically maintained at from 20°C to 60°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography, and the like to provide for compound 20A.
[0174] In the final step, the trimethylsilylethoxymethy (SEM) and t-butoxycarbonyl (t-BOC) protecting group are removed by conventional conditions. The SEM and t-BOC group are illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenyhnethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like could be used. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 21 A.
Figure imgf000083_0001
Scheme 5
[0175] As to the reaction in Scheme 5, in the first step, a Ni catalysed photoredox-catalyzed crossCoupling reaction, wherein at least a stoichiometric equivalent of a suitable amine, compound 22A is combined with compound 18A, under conventional reaction conditions [Angew. Chem., Int. Ed. 2019, 58, 6152-6163] well known in the art, including the use of (Ir(dF(CF3)ppy)2(dtbbpy))PFg and NiBn as co-catalysts usually in the presence of a base such as sodium carbonate, potassium carbonate, DABCO and the like. The reaction is typically conducted in an inert solvent such as DME, THF, DMF, and the like under a blue LED. The reaction is typically maintained at from 20°C to 60°C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography, and the like to provide for compound 23A.
[0176] In the final step, the trimethylsilylethoxymethy (SEM) protecting group is removed by conventional conditions. The SEM group are illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p- nitrobenzyloxycarbonyl and the like could be used. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 24 A.
Figure imgf000084_0001
[0177] As to the reaction in Scheme 6, in the first step, at least a stoichiometric amount of aminopyrazole, compound 9A, is combined with compound 13A under conventional amidation reaction conditions (Angewandte Chemie - International Edition, 2020, 59, 3028-3032) well known in the art including the use of N,N-dicyclohexylcarbodiimide (DCC), as an activation agent for the carboxyl group. Other activation agents are well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 0° to about 30° C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 25A.
[0178] In the final step, the ethyl formate and N- protecting groups are removed by conventional conditions, such as basic hydrolytic or acidic conditions to provide for compound 26A. The ethyl formate group is illustrative only and other conventional N-pyrazole protecting groups such as benzyl, tert-butyl and the like can be used. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPEC), and the like to provide for compound 26A.
Figure imgf000084_0002
Scheme 7 [0179] As to the reaction in Scheme 9, at least a stoichiometric amount of aminopyrazole, compound 9A, is combined with compound 27A under conventional amidation reaction conditions (Angewandte Chemie - International Edition, 2020, 59, 3028-3032) well known in the art including the use of N,N- dicyclohexylcarbodiimide (DCC), as an activation agent for the carboxyl group. Other activation agents are well known in the art. The reaction is typically conducted in an inert solvent such as chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 0° to about 30° C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 28 A.
[0180] With E3 and CDK2 coupling partners in hand, one skilled in the art can use known synthetic methods fortheir combination. Thus a library of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET/PK studies. As with the E3 binding moiety and CDK2 binding moiety, the final bifiinctional molecules can be subject to iterative design and optimization cycles in order to identify molecules with desirable properties.
[0181] In some instances, protecting group strategies and/or functional group interconversions (FGis) may be required to facilitate the preparation of the desired materials. Such chemical processes are well known to the synthetic organic chemist and many of these may be found in texts such as "Greene's Protective Groups in Organic Synthesis" Peter G. M. Wuts and Theodora W. Greene (Wiley), and "Organic Synthesis: The Disconnection Approach" Stuart Warren and Paul Wyatt (Wiley).
Figure imgf000086_0001
Scheme 8
[0182] As to the reaction in Scheme 8, at least a stoichiometric amount of a suitable amine, compound 26A is combined with compound 24A under conventional reductive amination reaction conditions well known in the art including the use of NaCNBtU. NaBH(OAc)3, NaBH4 and the like. The reaction is typically conducted in an inert solvent such as MeCN, MeOH, THF, and the like. The reaction is typically conducted at from about 0 °C to about 30 °C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like are optionally used to provide a compound of formula I.
Figure imgf000087_0001
Scheme 9
[0183] As to the reaction in Scheme 9, at least a stoichiometric amount of a suitable amine, compound 28A is combined with compound 21A under conventional reductive amination reaction conditions well known in the art including the use of NaCNBHs. NaBH(OAc)3, NaBPh and the like. The reaction is typically conducted in an inert solvent such as MeCN, MeOH, THF, and the like. The reaction is typically conducted at from about 0 °C to about 30 °C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like are optionally used to provide a compound of formula I.
Figure imgf000088_0001
Scheme 10
[0184] As to the reaction in Scheme 10, at least a stoichiometric amount of a suitable amine, compound 28A is combined with compound 17A under conventional reductive amination reaction conditions well known in the art including the use of NaCNBHs. NaBH(OAc)3, NaBtE and the like. The reaction is typically conducted in an inert solvent such as MeCN, MeOH, THF, and the like. The reaction is typically conducted at from about 0 °C to about 30 °C for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like are optionally used to provide a compound of formula I.
Methods of Use
[0185] The compounds and compositions described herein are useful in methods for treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part, by CDK2. In some embodiments, the CDK2 dependent disease or disorder is a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2. The methods comprise administering to a subject suffering from a CDK2 dependent disease or disorder an effective amount of a compound as described herein, e.g., a compound of formula F, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient.
[0186] Thus, there is provided a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient, for use in treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part, by CDK2, or is a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2. In one embodiment, there is provided a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient for use in treating an CDK2 dependent disease or disorder.
[0187] In one embodiment, there is provided a use of a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, in the preparation of a medicament for treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part, by CDK2, or is a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2.
[0188] In one embodiment, the method relates to a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient, for use in manufacture of a medicament for reducing CDK2 protein levels where reduction of such protein levels treats or ameliorates the disease or disorder.
[0189] In one embodiment, the methods described herein comprise use of a prodrug of a compound as described herein.
[0190] In one embodiment, the method relates a compound as described herein, e.g., a compound of formula I’, formula I, formula III, or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient wherein the CDK2 degradation at 1 pM concentration of the compound as described herein is in the range of about 25%-99%. The CDK2 degradation is measured by the assay described in the biological example. In some embodiments, the CDK2 degradation is from about 25% to about 50%, from about 45% to about 70%, from about 65% to about 90% or from about 75% to about 99%. In some embodiments, the CDK2 degradation is from about 25% to about 35%, from about 35% to about 45%, from about 45% to about 55%, from about 55% to about 65%, from about 65% to about 75%, from about 75% to about 85%, from about 85% to about 99%. In some embodiments, the CDK2 degradation is more than 60%. In some embodiments, the CDK2 degradation is more than 70%. In some embodiments, the CDK2 degradation is more than 80%. In some embodiments, the CDK2 degradation is more than 90%.
[0191] The compounds and compositions described herein are useful in treating CDK2 dependent diseases or disorders such as cancers including, but not limited to, liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein- Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma (e.g., diffuse large B-cell lymphoma). The cancer may be selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma. In one embodiment, the CDK2 -dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triplenegative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST). In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple -negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the CDK2 -dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite stable colorectal cancer (mssCRC). In certain embodiments, compounds or compositions described herein are active against solid tumors.
[0192] The compounds of the disclosure can be administered in effective amounts to treat or prevent or reduce the risks of developing a disease or disorder as discussed herein and/or to prevent or reduce the rate of the development or progression thereof in a subject.
[0193] In general, methods of using the compounds of the present application comprise administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.
[0194] In certain embodiments, compounds as described herein are useful in the treatment of proliferative disorders (e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, levels of cell proteins of interest, e.g., pathogenic and oncogenic proteins are modulated, or their growth is inhibited or the proteins are degraded by contacting said cells with an compound or composition, as described herein. In other embodiments, the compounds are useful in treating cancer. [0195] Thus, in another aspect of the application, methods for the treatment of cancer are provided comprising administering a therapeutically effective amount of a compound or composition, as described herein, to a subject in need thereof. In certain embodiments, a method for the treatment of cancer is provided comprising administering a therapeutically effective amount of a compound, or a pharmaceutical composition comprising a compound as described herein to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result. In some embodiments, the compounds of present application are administered orally or intravenously. In certain non-limiting embodiments of the present application a “therapeutically effective amount” of the compound or pharmaceutical composition is that amount effective for killing or inhibiting the growth of tumor cells. The compounds and compositions, according to the method of the present application, may be administered using any amount and any route of administration effective for killing or inhibiting the growth of tumor cells. Thus, the expression “amount effective to kill or inhibit the growth of tumor cells,” as used herein, refers to a sufficient amount of agent to kill or inhibit the growth of tumor cells. 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 disease, the particular anticancer agent, its mode of administration, and the like.
[0196] Another aspect of the application relates to a method of treating or lessening the severity of a disease or condition associated with a proliferation disorder in a patient, said method comprising a step of administering to said patient, a compound described herein (e.g., compound of formula I’, formula I, or formula III) or a composition comprising said compound.
[0197] It will be appreciated that the compounds and compositions, according to the method of the present application, may be administered using any amount and any route of administration effective for the treatment of cancer and/or disorders associated with cell hyperproliferation. For example, when using the compounds for the treatment of cancer, the expression “effective amount” as used herein, refers to a sufficient amount of agent to inhibit proliferation, or refers to a sufficient amount to reduce the effects of cancer. 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 diseases, the particular anticancer agent, its mode of administration, and the like.
[0198] The present application also provides methods of protecting against a proliferative disorder in a subject in need thereof or the treatment of a proliferative disorder in a subject in need thereof by administering a therapeutically effective amount of compound or composition as described herein to a subject in need of such treatment. The proliferative disorder can be cancer or a precancerous condition. The present application also provides the use of compound as described herein for the preparation of a medicament useful for the prevention of a proliferative disorder.
[0199] As used herein, the term “proliferative disorder” refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous. Exemplary proliferative disorders of the application encompass a variety of conditions wherein cell division is deregulated. Exemplary proliferative disorder include, but are not limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term “rapidly dividing cell” as used herein is defined as any cell that divides at a rate that exceeds or is greater than what is expected or observed among neighboring or juxtaposed cells within the same tissue. A proliferative disorder includes a precancer or a precancerous condition. A proliferative disorder includes cancer. The methods provided herein are used to treat or alleviate a symptom of cancer. The term “cancer” includes solid tumors, as well as, hematologic tumors and/or malignancies. A “precancer cell” or “precancerous cell” is a cell manifesting a proliferative disorder that is a precancer or a precancerous condition. A “cancer cell” or “cancerous cell” is a cell manifesting a proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers.
[0200] Exemplary non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gramnegative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.
[0201] A “proliferative disorder of the hematologic system” is a proliferative disorder involving cells of the hematologic system. A proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. A proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system. [0202] One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Erma et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the application.
[0203] In certain embodiments, according to the methods of treatment of the present application, levels of cell proteins of interest, e.g., pathogenic and oncogenic proteins are modulated, or their growth is inhibited by contacting said cells with an compound or composition, as described herein. In other embodiments, the compounds are useful in treating cancer.
[0204] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds described herein, and methods of treating a subject using such derivative, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents. [0205] Other therapies or anticancer agents that may be used in combination with the compounds and compositions disclosed herein including surgery, radiotherapy, endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabine, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), to name a few. For a more comprehensive discussion of overview of cancer therapy see The Merck Manual, Twentieth Ed. 2020, the entire contents of which are hereby incorporated by reference. See also the National Cancer Institute (NCI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA) website for a list of the FDA approved oncology drugs (www.fda.gov/cder/cancer/druglistfirame).
[0206] In certain embodiments, a pharmaceutical composition as described herein, comprising a compound as disclosed herein, further comprise one or more additional therapeutically active ingredients (e.g., a chemotherapeutic agent and/or a palliative agent). For purposes of the application, the term “palliative” refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not considered to be curative. For example, palliative treatments encompass painkillers, antinausea medications and anti-sickness drugs. In addition, chemotherapy, radiotherapy and surgery can all be used palliatively (that is, to reduce symptoms without going for cure; e.g., for shrinking tumors and reducing pressure, bleeding, pain and other symptoms of cancer).
Administration, Pharmaceutical Compositions
[0207] Administration of the disclosed compounds and pharmaceutical compositions can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
[0208] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula I’, Formula I, or Formula III, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, diluent, or surfactant.
[0209] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, timerelease capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
[0210] Illustrative pharmaceutical compositions for oral administration include tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes, and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200. Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.
[0211] Illustrative liquid pharmaceutical compositions, such as injectable compositions can, for example, be prepared by dissolution, dispersion, etc. For example, a compound as described herein can be dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds. Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectable s can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
[0212] The disclosed compounds can be formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
[0213] The disclosed compounds can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a fdm of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564, which is hereby incorporated by reference in its entirety.
[0214] Disclosed compounds can be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, poly orthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a poly carboxy lie acid polymer, or a polyacrylate.
[0215] In one embodiment, the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present disclosure. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
[0216] The kit of the disclosure may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the disclosure typically comprises directions for administration.
[0217] Pharmaceutical dosage forms of a compound of this disclosure may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray-drying, levigating, emulsifying, (nano-/micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of this disclosure can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
[0218] As noted above, the compositions are comprised of, in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are nontoxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
[0219] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
[0220] Compressed gases may be used to disperse a compound of this disclosure in an aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
[0221] The compositions of this disclosure may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of this disclosure that can be formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
[0222] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below. Formulation Examples
[0223] The following are representative pharmaceutical formulations containing a compound of this disclosure.
Formulation Example 1 — Tablet formulation
[0224] The following ingredients are mixed intimately and pressed into single scored tablets.
Quantity per
Ingredient tablet, mg compound of this disclosure 400
Cornstarch 50 croscarmellose sodium 25
Lactose 120 magnesium stearate 5
Formulation Example 2 — Capsule formulation
[0225] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Quantity per
Ingredient capsule, mg compound of this disclosure 200 lactose, spray-dried 148 magnesium stearate 2
Formulation Example 3 — Suspension formulation
[0226] The following ingredients are mixed to form a suspension for oral administration.
Ingredient Amount compound of this disclosure 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.0 g sorbitol (70% solution) 13.00 g
V eegum K (V anderbilt Co . ) 1.0 g
Flavoring 0.035 mL
Colorings 0.5 mg distilled water q.s. to 100 mL
Formulation Example 4 — Injectable formulation
[0227] The following ingredients are mixed to form an injectable formulation.
Ingredient Amount compound of this disclosure 0.2 mg -20 mg sodium acetate buffer solution, 0.4 M 2.0 mL
HC1 (IN) or NaOH (IN) q.s. to suitable pH water (distilled, sterile) q.s. to 20 mL
Formulation Example 5 — Suppository Formulation
[0228] A suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
Ingredient Amount
Compound of this disclosure 500 mg
Witepsol® H-15 balance
Dosing
[0229] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian can determine and prescribe an effective amount of a compound as described herein to treat or prevent the disease or disorder presented.
[0230] Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored.
EXAMPLES
[0231] This disclosure is further understood by reference to the following examples, which are intended to be purely exemplary of this disclosure. This disclosure is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of this disclosure only. Any methods that are functionally equivalent are within the scope of this disclosure. Various modifications of this disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications fall within the scope of the present disclosure.
[0232] In the specification and in the examples below, all temperatures are in degrees Celsius. In addition, the following abbreviations have the following meanings. If not defined, these abbreviations have their art recognized meaning.
Abbreviation Meaning
5 chemical shift (ppm)
ACN or MeCN acetonitrile
Boc tert -butoxycarbonyl
BRET Bioluminescence Resonance Energy Transfer
BuLi n-butyllithium
Cbz benzyloxycarbonyl
CbzCl Benzyloxycarbonyl chloride
DC50 concentration that resulted in a 50% targeted protein degradation
DCM dichloromethane
DHA docosahexaenoic acid
DIEA or DIPEA diisopropylethylamine
DMA dimethylacetamide
DMAP 4-dimethylaminopyridine
DMF N,N -dimethylformamide
DMP Dess-Martin periodinane
DMSO dimethylsulfoxide d6-DMSO deuterated dimethylsulfoxide d4-MeOH deuterated methanol dtbbpy 4,4'-di-tert-butyl-2,2'-dipyridyl
EDCI 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide EPA eicosapentaenoic acid eq. equivalent(s)
ESI electrospray ionization
EtOAc ethyl acetate
EtOH ethanol
FBS fetal Bovine Serum
FITC fluorescein isothiocyanate
Fmoc fluorenylmethyloxycarbonyl g grams
’H NMR proton nuclear magnetic resonance spectroscopy h hour(s)
HPLC high performance liquid chromatography
IPA isopropyl alcohol
Ir[(dF(CF3)ppy)2dtbbpy]PF6 [4,4'-Bis(l,l-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-
2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate
JohnPhos (2-biphenylyl)di-tert-butylphosphine
L liter
LC liquid chromatography
LC-MS liquid chromatography - mass spectrometry
M molar mCPBA meta-chloroperoxybenzoic acid
MeOH methanol mg milligram mmol millimole mL milliliter pL microliter nmol or pmol micromole mM micromolar pm micron m/z mass-to-charge ratio
MsOH methanesulfonic acid min minute(s)
NiCh glyme Nickel(II) chloride ethylene glycol dimethyl ether complex nm nanometer N normal PBS Phosphate-buffered saline Pd2(dba)3 tris(dibenzylideneacetone)dipalladinm(0) Pd(OAc)2 palladium (II) acetate pM picomolar q.s. amount which is sufficient rt room temperature SEM trimethylsilylethoxymethyl SFC supercritical fluid chromatography t-Bu tert-butyl TEA triethylamine TFA trifluoroacetic acid TFP tri(2-furyl)phosphine THF tetrahydrofuran TMP 2,2,6,6-tetramethylpiperidine T3P propanephosphonic acid anhydride TRITC tetramethylrhodamine TsCl 4-toluenesulfonyl chloride TsOH 4-toluenesulfonic acid
UV ultraviolet v/v volume/volume ratio weight percent
NMR abbreviations br = broad d = doublet dd = doublet of doublets m = multiplet q = quartet quin = quintet s = singlet t = triplet
Example 1: Synthesis of (lR,3S)-3-(3-(2-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)acetamido)-lH-pyrazol-5-yl)cyclopentyl (2S)-2- methylazetidine-l-carboxylate (Compound P-8)
Figure imgf000102_0001
[0233] To a solution of methyl 3-oxocyclopentane-l-carboxylate (25 g, 175.87 mmol, 1 eq) in methanol (125 mL) was added 4-methylbenzenesulfonic acid hydrate (6.69 g, 35.17 mmol, 0.2 eq) and trimethoxymethane (111.98 g, 1.06 mol, 115.68 mL, 6 eq) at 20°C. The mixture was stirred at 20°C for 16 hours. The reaction mixture was poured into a NaHCCf sat solution (200 mL) and then the mixture was concentrated under reduced pressure to remove methanol. The residue was extracted with ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to give methyl 3,3-dimethoxycyclopentane-l-carboxylate which was carried forward without purification. ’H NMR (400 MHz, CDCh) 5 1.71-1.93 (m, 4H), 1.97-2.08 (m, 2H), 2.82 (quin, J=8.25 Hz, 1H), 3.14 (d, J=7.75 Hz, 6H), 3.61 (s, 3H).
Step 2:
Figure imgf000103_0001
[0234] To a solution of n-BuLi (2.5 M, 403.78 mL, 2 eq) in tetrahydrofuran (360 mL) at -65 °C, was added acetonitrile (41.44 g, 1.01 mol, 53.13 mL, 2 eq) dropwise, the internal reaction temperature was maintained below -55 °C. The mixture was stirred at -65 °C for 1 hour. A solution of methyl 3,3- dimethoxy cyclopentane- 1 -carboxylate (95 g, 504.73 mmol, 1 eq) in tetrahydrofuran (135 mL) was added. The mixture was stirred at -65 °C for 1 hour, then the reaction was warmed to 0 °C. Water (500 mL) was added slowly and the reaction stirred for 1 hour. IN HC1 solution was added to the mixture until the pH = 7. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran. The aqueous mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over sodium sulfate and concentrated in vacuo to give 3-(3,3-dimethoxycyclopentyl)-3-oxopropanenitrile which was carried forward without purification. ‘H NMR (400 MHz, CDCh) 5 1.77-1.87 (m, 3H), 1.91-1.98 (m, 1H), 1.98-2.04 (m, 3H), 3.15 (d, 7=1.75 Hz, 6H), 3.53 (s, 2H).
Step 3:
Figure imgf000103_0002
[0235] To a suspension of 3-(3,3-dimethoxycyclopentyl)-3-oxopropanenitrile (36.39 g, 292.04 mmol, 1.2 eq, HC1) in ethanol (465 mL) was added saturated aqueous solution of sodium hydroxide (11.68 g, 292.04 mmol, 1.2 eq) and stirred for 1 h. To the mixture was added a solution of 3-(3, 3- dimethoxycyclopentyl)-3-oxo-propanenitrile (48 g, 243.37 mmol, 1 eq) in ethanol (200 mL). The mixture was warmed to 75 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give residue. The residue was purified by column chromatography (SiCL, 0 to 100% ethyl acetate in petroleum ether) to give l-(tert-butyl)-3-(3,3-dimethoxycyclopentyl)-lH-pyrazol-5-amine. ’H NMR (400 MHz, CDCL) 5 1.60 (s, 9H), 1.66-1.79 (m, 2H), 1.80-1.87 (m, 2H), 1.92-2.01 (m, 1H), 2.26 (dd, 7=13.27, 8.13 Hz, 1H), 3.08-3.18 (m, 1H), 3.20-3.24 (m, 6H), 3.45-3.53 (m, 2H), 5.42 (s, 1H).
Step 4:
Figure imgf000104_0001
[0236] To a solution of l-(tert-butyl)-3-(3,3-dimethoxycyclopentyl)-lH-pyrazol-5-amine (28 g, 104.73 mmol, 1 eq) in acetonitrile (280 mL) at 0°C was added CbzCl (35.73 g, 209.45 mmol, 29.78 mL, 2 eq). The mixture was warmed to room temperature and stirred for 2 hours. NaHC’CL (28.15 g, 335.12 mmol, 13.03 mL, 3.2 eq) was added and the mixture was stirred for 14 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give benzyl (l-(tert-butyl)-3- (3,3-dimethoxycyclopentyl)-lH-pyrazol-5-yl)carbamate which was carried forward without purification. ’H NMR (400 MHz, CDCh) 5 1.44 (s, 9H), 1.92 (br s, 2H), 2.09 (br d, J=9.43 Hz, 2H), 2.19-2.24 (m, 2H), 4.46 (s, 2H), 5.06 (s, 2H), 5.91-5.99 (m, 1H), 7.24 (br d, J=1.23 Hz, 5H).
Step 5:
Figure imgf000104_0002
[0237] To a solution of benzyl (l-(tert-butyl)-3-(3,3-dimethoxycyclopentyl)-lH-pyrazol-5- yl)carbamate (47 g, 117.06 mmol, 1 eq) in acetone (200 mL) and water (200 mL) was added TsOH (2.62 g, 15.22 mmol, 0.13 eq). The mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature and was concentrated under reduced pressure to remove acetone. The aqueous solution was extracted with dichloromethane (3 x 100 mL). The organic phases were combined and washed with brine (3 x 100 mL), dried over sodium sulfate and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiCL, 0 to 25% ethyl acetate in petroleum ether) to give a solid. The solid was triturated with methyl tertiary butyl ether (150 mL) to give benzyl (l-(tert-butyl)-3-(3-oxocyclopentyl)-lH-pyrazol-5-yl)carbamate. rH NMR (400 MHz, CDCh) 5 1.58 (s, 9H), 1.99-2.11 (m, 1H), 2.16-2.26 (m, 1H), 2.31-2.40 (m, 2H), 2.47 (d, J=9.01 Hz, 1H), 2.55 (d, J=7.88 Hz, 1H), 3.37-3.47 (m, 1H), 5.20 (s, 2H), 6.10 (br s, 1H), 7.38 (br s, 5H).
Step 6:
Figure imgf000104_0003
[0238] A solution of benzyl (l-(tert-butyl)-3-(3-oxocyclopentyl)-lH-pyrazol-5-yl)carbamate (25 g, 70.34 mmol, 1 eq) in tetrahydrofuran (250 mL) was degassed and purged with nitrogen three times and cooled to -78 °C. Lithium triethylborohydride (1.0 M, 140.67 mL, 2 eq) was added dropwise at a rate to maintain the internal temperature below -55 °C. The mixture was stirred at -65 °C for 1.5 hours. Methanol (500 mL) was added between 0-10 °C and then stirred for 1 h. The reaction was concentrated in vacuo to give residue. The residue was dissolved in water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine (3 x 200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiCL, 0 to 50% ethyl acetate in petroleum ether) to give benzyl ( I -(tcrt-bnty l )-3 -((cz.s )- 3-hydroxycyclopentyl)-lH-pyrazol-5-yl)carbamate. H NMR (400 MHz, CDCh) 5 1.55 (s, 9H), 1.74- 1.85 (m, 2H), 1.86-1.93 (m, 2H), 2.00-2.12 (m, 2H), 3.16-3.27 (m, 1H), 4.34 (br d, J=3.38 Hz, 1H), 4.96-5.07 (m, 1H), 5.19 (s, 2H), 6.06 (br s, 1H), 6.51 (br s, 1H), 7.33-7.41 (m, 5H) and benzyl (l-(tert- butyl)-3-((lra«5)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)carbamate. ’H NMR (400 MHz, CDCh) 5 1.58 (s, 9H), 1.61-1.77 (m, 3H), 1.88-1.97 (m, 1H), 1.98-2.03 (m, 1H), 2.03-2.12 (m, 1H), 2.12-2.25 (m, 1H), 3.31-3.42 (m, 1H), 4.46 (t, J=5.57, 2.71 Hz, lH), 5.19 (s, 2H), 6.04 (br s, 1H), 6.30 (br s, 1H), 7.37 (br s, 5H).
Step 7:
Figure imgf000105_0001
[0239] The racemic mixture of benzyl ( l-(tcrt-butyl)-3-((c/.s)-3-hydroxycyclopcntyl)- I H-pyrazol-5- yl)carbamate (6 g, 16.79 mmol, 1 eq) was purified into pure enantiomers by chiral SFC (column: DAICEL CHIRALPAK IG (250 mmx50 mm, 10 pm); mobile phase: [0.1% NH4OH in MeOH]; B% CO2: 25%-25%, 3 min) to give benzyl (l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5- yl)carbamate. ’H NMR (400 MHz, CDCh) 5 1.46 (s, 9H), 1.52 (br d, J=9.76 Hz, 1H), 1.59-1.84 (m, 4H), 1.85-2.01 (m, 3H), 3.08-3.16 (m, 1H), 4.24 (br s, 1H), 4.81 (br s, 1H), 5.O9 (s, 2H), 5.97 (br s, 1H), 6.16 (br s, 1H), 7.16 (s, 1H) and benzyl (l-(tert-butyl)-3-((lR,3S)-3-hydroxycyclopentyl)-lH-pyrazol- 5-yl)carbamate. ‘H NMR (400 MHz, CDC13) 5 1.45 (s, 9H), 1.49-1.59 (m, 1H), 1.59-1.85 (m, 3H), 1.85- 2.02 (m, 3H), 3.08-3.16 (m, 1H), 4.18-4.29 (m, 1H), 4.67-4.99 (m, 1H), 5.05-5.13 (m, 2H), 5.97 (br s, 1H), 6.32 (br s, 1H), 7.27 (br s, 4H).
Step 8:
Figure imgf000105_0002
[0240] To a solution of benzyl (l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5- yl)carbamate (1 g, 2.80 mmol, 1 eq) in DCM (15 mL) was added pyridine (663.88 mg, 8.39 mmol, 677.43 pL, 3 eq), DMAP (34.18 mg, 279.76 pmol, 0.1 eq) and a solution of (4- nitrophenyl)carbonochloridate (845.85 mg, 4.20 mmol, 1.5 eq) in DCM (5 mL). The reaction was stirred for 12 hours at room temperature. The solvents were evaporated in vacuo to give a residue. The residue was purified by column chromatography (SiCL, 25% ethyl acetate in petroleum ether) to give benzyl (l-(tert-butyl)-3-((lS,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-lH-pyrazol-5- yl)carbamate. m/z (ESI+) 523 (M+H)+. ‘H NMR (400 MHz, CDC13) 5 1.60 (s, 9 H), 1.84 - 2.05 (m, 4 H), 2.08 - 2.16 (m, 1 H), 2.52 - 2.68 (m, 1 H), 3.04 - 3.23 (m, 1 H), 5.22 (s, 3 H), 6.07 - 6.41 (m, 2 H), 7.32 - 7.56 (m, 7 H), 8.27 (d, J=9.26 Hz, 2 H).
Step 9:
Figure imgf000106_0001
[0241] A solution of benzyl (l-(tert-butyl)-3-((lS,3R)-3-(((4- nitrophenoxy)carbonyl)oxy)cyclopentyl)-lH-pyrazol-5-yl)carbamate (250 mg, 478.42 pmol, 1 eq) in formic acid (3 mL) was stirred at 80 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by chromatography (SiCL, 25% ethyl acetate in petroleum ether) to give benzyl (3-((lS,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-lH- pyrazol-5-yl)carbamate. m/z (ESI+) 467 (M+H)+. ‘H NMR (400 MHz, CDC13) 5 1.86 - 2.03 (m, 3 H), 2.09 - 2.23 (m, 2 H), 2.54 - 2.64 (m, 1 H), 3.20 (br t, J=8.34 Hz, 1 H), 5.20 (s, 2 H), 5.29 (dt, J=5.81, 2.88 Hz, 1 H), 6.37 (br s, 1 H), 7.29 - 7.42 (m, 7 H), 7.83 (br s, 1 H), 8.27 (d, J=9.18 Hz, 2 H).
Step 10:
Figure imgf000106_0002
[0242] To a solution of benzyl (3-((lS,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-lH- pyrazol-5-yl)carbamate (150 mg, 321.58 pmol, 1 eq) and DIPEA (207.81 mg, 1.61 mmol, 280.06 pL, 5 eq) in THF (7 mL) was added (S)-2-methylazetidine hydrochloride (121.09 mg, 1.13 mmol, 3.5 eq, HCI) at 20°C. The mixture was stirred for 4 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (10 ml), and was washed with IM sodium hydroxide (3 x 5 mL) and brine (5 mL) . The organic layer was dried over sodium sulfate, fdtered and concentrated to (lR,3S)-3-(5-(((benzyloxy)carbonyl)amino)-lH-pyrazol-3-yl)cyclopentyl (S)-2- methylazetidine-1 -carboxylate, m/z (ESI+) 399 (M+H)+. ’H NMR (400 MHz, CDC13) 5 1.29 (br s, 3 H), 1.73 - 1.88 (m, 5 H), 1.99 - 2.07 (m, 1 H), 2.19 - 2.30 (m, 1 H), 2.31 - 2.44 (m, 1 H), 3.08 (quin, J=8.05 Hz, 1 H), 3.79 (br t, J=1.63 Hz, 2 H), 4.20 - 4.31 (m, 1 H), 5.06 - 5.11 (m, 1 H), 5.13 (s, 2 H), 7.26 - 7.34 (m, 4 H), 7.75 (br s, 1 H). Step 11:
Figure imgf000107_0001
[0243] To a solution of (lR,3S)-3-(5-(((benzyloxy)carbonyl)amino)-lH-pyrazol-3-yl)cyclopentyl (S)- 2 -methylazetidine- 1 -carboxylate (60 mg, 150.58 pmol, 1 eq) in dioxane (10 mb) was added 10% Pd/C (0.1 g) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 ( 15psi) for 12 hours. The solution was fdtered through celite. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 25°C to give (lR,3S)-3-(5-amino-lH-pyrazol-3-yl)cyclopentyl (S)-2 -methylazetidine- 1- carboxylate. m/z (ESI+) 265 (M+Na)+. ‘HNMR (400 MHz, d6-DMSO) 5 1.29 (d, J=6.20 Hz, 3 H), 1.52 - 1.98 (m, 6 H), 2.22 - 2.40 (m, 2 H), 2.80 - 3.01 (m, 1 H), 3.74 (br d, J=7.03 Hz, 2 H), 4.13 - 4.31 (m, 1 H), 4.44 (br s, 1 H), 4.85 - 5.01 (m, 1 H), 5.17 (s, 1 H), 11.08 (br s, 1 H).
Step 12:
Figure imgf000107_0002
[0244] A solution of l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidine-4- carbaldehyde [synthesis of 1 -(2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)piperidine-4- carbaldehyde is described in WO2021/113557 and is commercially available from Princeton BioMolecular Research, CAS # 2241315-66-0] (280 mg, 758.05 pmol, 1 eq), tert-butyl 2-(piperidin-4- yl)acetate (181.28 mg, 909.66 pmol, 1.2 eq), NaOAc (62.18 mg, 758.05 pmol, 1 eq) and AcOH (45.52 mg, 758.05 pmol, 43.35 pL, 1 eq) in DMA (10 mb) was stirred at 50 °C for 2 hours. NaBFLCN (95.27 mg, 1.52 mmol, 2 eq) was added to the mixture. The reaction was stirred at 50 °C for 12 hours. Water (3mL) was added to the mixture and stirred at 20 °C for 1 h. The mixture was purified by HPLC (Phenomenex Luna Cis 100x40mm><3 pm; mobile phase: 35%-65%, 1% formic aid in water-ACN) to give tert-butyl 2-( 1 -(( 1 -(2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)piperidin-4- yl)methyl)piperidin-4-yl)acetate. rH NMR (400 MHz, cU-MeOD) 5 1.23 - 1.40 (m, 4 H), 1.45 (s, 10 H), 1.71 - 1.97 (m, 6 H), 2.05 - 2.23 (m, 4 H), 2.26 - 2.52 (m, 2 H), 2.62 - 2.91 (m, 4 H), 2.95 - 3.07 (m, 3 H), 4.05 (br d, J=13.01 Hz, 2 H), 5.06 (dd, J=12.44, 5.44 Hz, 1 H), 7.21 (dd, J=8.63, 2.25 Hz, 1 H), 7.34 (d, .7=2,25 Hz, 1 H), 7.66 (d, J=8.50 Hz, 1 H).
Step 13:
Figure imgf000108_0001
[0245] To a mixture of tert-butyl 2-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidin-4-yl)acetate (100 mg, 180.94 pmol, 1 eq) in DCM (1.5 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 37.32 eq). The mixture was stirred at 20 °C for 3 hours. The reaction was concentrated under reduce pressure to give 2-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)acetic acid which was carried forward directly.
Step 14:
Figure imgf000108_0002
[0246] To a mixture (lR,3S)-3-(5-amino-lH-pyrazol-3-yl)cyclopentyl (S)-2 -methylazetidine- 1- carboxylate (53.23 mg, 201.39 pmol, 1 eq), 2-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin- 5-yl)piperidin-4-yl)methyl)piperidin-4-yl)acetic acid (80 mg, 161.11 pmol, 0.8 eq) and DIEA (130.14 mg, 1.01 mmol, 175.39 pL, 5 eq) in DCM (0.5 mL) was added T3P (640.78 mg, 1.01 mmol, 598.86 pL, 50% purity, 5 eq). The mixture was stirred at 20 °C for 12 hours. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (Phenomenex Luna Cis 75 mm x 30 mm x 3 pm; mobile phase: 10%-40%, 1% formic acid in water-ACN) to give (lR,3S)-3-(3-amino-l-(2-(l-((l-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)acetyl)-lH- pyrazol-5-yl)cyclopentyl (2S)-2-methylazetidine-l-carboxylate. 1HNMR(400 MHz, di-McOD) 5 1.36 (br d, 7=5.50 Hz, 3 H), 1.42 (br dd, 7=12.01, 2.88 Hz, 2 H), 1.63 (br d, 7=13.63 Hz, 2 H), 1.75 - 1.86 (m, 3 H), 1.86 - 1.94 (m, 4 H), 1.96 (br d, 7=4.25 Hz, 1 H), 2.04 (br s, 1 H), 2.09 (br d, 7=2.50 Hz, 1 H), 2.12 (br dd, 7=7.13, 4.50 Hz, 2 H), 2.15 - 2.25 (m, 2 H), 2.33 - 2.37 (m, 1 H), 2.40 (d, 7=6.88 Hz, 2 H), 2.50 (br d, 7=5.63 Hz, 1 H), 2.68 - 2.74 (m, 1 H), 2.76 (br d, 7=2.75 Hz, 1 H), 2.80 - 2.89 (m, 1 H), 2.96 - 3.10 (m, 5 H), 3.18 (brt, 7=8.19 Hz, 1 H), 3.65 (br d, 7=10.51 Hz, 2 H), 3.85 (brt, 7=7.63 Hz, 2 H), 4.09 (br d, 7=13.38 Hz, 2 H), 4.34 (br d, 7=8.13 Hz, 1 H), 5.01 - 5.14 (m, 2 H), 6.35 (s, 1 H), 7.24 (dd, 7=8.63, 2.25 Hz, 1 H), 7.37 (d, 7=2.13 Hz, 1 H), 7.68 (d, 7=8.50 Hz, 1 H). Example 2: Synthesis of (lR,3S)-3-(3-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)methyl)phenyl)acetamido)-lH-pyrazol-5-yl)cyclopentyl (2S)-2- methylazetidine-l-carboxylate (Compound P-11)
Figure imgf000109_0002
[0247] A solution of 2-(4-formylphenyl)acetic acid (100 mg, 609.17 pmol, 1 eq), 2-(2,6- dioxopiperidin-3-yl)-5-(piperazin-l-yl)isoindoline-l, 3-dione (250.26 mg, 731.00 pmol, 1.2 eq), NaOAc (49.97 mg, 609.17 umol, 1 eq) and HOAc (36.58 mg, 609.17 pmol, 34.84 pL, 1 eq) in DMA (10 mL) was stirred at 50°C for 2 hours. NaBH3CN (76.56 mg, 1.22 mmol, 2 eq) was added. The resulting solution was stirred for 12 hours at 50°C. The mixture was quenched with water (0.1 mL). The mixture was purified by pre-HPLC [Phenomenex Luna Cis 100 mm x 40 mm x 3 pm; 25 to 55% 1% formic acid in water in ACN] and lyophilized to give 2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)piperazin-l-yl)methyl)phenyl)acetic acid. ’H NMR (400 MHz, di-McOD) 52.06 - 2.15 (m, 1 H), 2.67 - 2.79 (m, 2 H), 2.81 - 2.97 (m, 5 H), 3.54 (br d, 7=4.63 Hz, 4 H), 3.62 (s, 2 H), 3.84 (s, 2 H), 5.07 (dd, 7=12.51, 5.50 Hz, 1 H), 7.22 - 7.43 (m, 6 H), 7.70 (d, 7=8.50 Hz, 1 H).
Step 2:
Figure imgf000109_0001
[0248] To a mixture of 2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l- yl)methyl)phenyl)acetic acid (30 mg, 61.16 pmol, 0.8 eq), (lR,3S)-3-(5-amino-lH-pyrazol-3- yl)cyclopentyl (S)-2 -methylazetidine- 1 -carboxylate (20.21 mg, 76.45 pmol, 1 eq) and DIEA (49.40 mg, 382.25 pmol, 66.58 pL, 5 eq) in DCM (1 mL) was added T3P (243.25 mg, 382.25 pmol, 227.34 pL, 50% purity, 5 eq). The mixture was stirred at 20°C for 12 hours. The mixture was concentrated to give a residue. The crude product was purified by prep-HPLC [Phenomenex Luna Cis 75 mm x 30 mm x 3 pm; 15 to 35% 1% formic acid in water to ACN] and lyophilized to give (lR,3S)-3-(3-(2-(4-((4-(2- (2,6-dioxopiperidin-3-yl)- 1 ,3-dioxoisoindolin-5-yl)piperazin- 1 -yl)methyl)phenyl)acetamido)- 1H- pyrazol-5-yl)cyclopentyl (2S)-2-methylazetidine-l-carboxylate. ’H NMR (400 MHz, d-i-McOD) 5 1.27 - 1.42 (m, 3 H), 1.74 - 2.15 (m, 7 H), 2.27 - 2.47 (m, 2 H), 2.65 - 2.79 (m, 5 H), 2.80 - 2.91 (m, 1 H), 3.07 (br t, 7=8.07 Hz, 1 H), 3.49 (br s, 4 H), 3.68 (br s, 2 H), 3.82 (br t, 7=7.63 Hz, 2 H), 4.26 - 4.39 (m, 3 H), 5.02 - 5.13 (m, 2 H), 5.29 (s, 1 H), 7.23 (br d, 7=8.50 Hz, 1 H), 7.36 (s, 5 H), 7.68 (d, 7=8.50 Hz, 1 H), 8.28 (s, 1 H).
Example 3: Synthesis of (lR,3S)-3-(3-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperazine-l-carbonyl)phenyl)acetamido)-lH-pyrazol-5-yl)cyclopentyl (2S)-2- methylazetidine-l-carboxylate (Compound P-15)
Figure imgf000110_0001
[0249] To a solution of 3 -(l-oxo-5 -(piperazin- l-yl)isoindolin-2-yl)piperidine-2, 6-dione (700 mg, 2.13 mmol, 1 eq) and 4-(2-(tert-butoxy)-2-oxoethyl)benzoic acid (1.01 g, 4.26 mmol, 2 eq) in DCM (10 mb) was added T3P (3.39 g, 10.66 mmol, 3.17 mb, 5 eq) and DIEA (1.38 g, 10.66 mmol, 1.86 mL, 5 eq). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give tert-butyl 2-(4-(4-(2- (2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine-l-carbonyl)phenyl)acetate which was used in next step directly without purification. rH NMR (400 MHz, di-MeOD) 5 0.96 - 1.14 (m, 2 H), 1.16 - 1.31 (m, 1 H), 1.33 - 1.40 (m, 5 H), 1.41 - 1 .48 (m, 9 H), 1.60 - 1.86 (m, 2 H), 2.08 - 2.21 (m, 1 H), 2.45 (qd, 7=13.20, 4.69 Hz, 1 H), 2.71 - 2.82 (m, 1 H), 2.82 - 2.97 (m, 1 H), 3.22 (q, J=1.42 Hz, 1 H), 3.59 - 3.66 (m, 2 H), 4.32 - 4.48 (m, 1 H), 5.10 (dd, 7=13.26, 5.13 Hz, 1 H), 7.07 - 7.16 (m, 1 H), 7.32 - 7.49 (m, 3 H), 7.65 (d, 7=8.50 Hz, 1 H), 7.92 - 8.07 (m, 1 H). Step 2:
Figure imgf000111_0001
[0250] To a solution of tert-butyl 2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperazine-l-carbonyl)phenyl)acetate (1.8 g, 3.29 mmol, 1 eq) in DCM (20 mb) was added TFA (10.78 g, 94.54 mmol, 7 mb, 28.71 eq) .The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC [Phenomenex Luna Cis 250 x 50mm x 10 pm; 10 to 40%, 1% TFA in water to ACN] and lyophilized to give 2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine-l- carbonyl)phenyl)acetic acid, m/z (ESI+) 419.2 (M+H)+.
Step 3:
Figure imgf000111_0002
[0251] To a solution of 2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine-l- carbonyl)phenyl)acetic acid (50 mg, 101.94 pmol, 0.8 eq), [(lR,3S)-3-(3-amino-lH-pyrazol-5- yl)cyclopentyl] (2R)-2 -methylazetidine- 1 -carboxylate (33.68 mg, 127.42 pmol, 1 eq) in pyridine (1.5 mb) was added EDCI (48.85 mg, 254.84 pmol, 2 eq). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC [Phenomenex Luna Cis 150 x 30mm x 5 pm; 1 to 30%, 1% TFA in water to ACN] and lyophilized to give (lR,3S)-3-(3-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperazine- 1 -carbonyl)phenyl)acetamido)- lH-pyrazol-5-yl)cyclopentyl (2S)-2 -methylazetidine- 1 - carboxylate. ’H NMR (400 MHz, d4-MeOD) 5 1.28-1.38 (m, 3H), 1.76-1.97 (m, 5H), 2.07-2.21 (m, 2H), 2.34 (br dd, 7=10.63, 7.75 Hz, 1H), 2.41-2.54 (m, 2H), 2.80 (br s, 1H), 2.88 (br d, 7=13.26 Hz, 1H), 3.13-3.23 (m, 2H), 3.65 (br s, 3H), 3.76 (s, 2H), 3.83 (br t, 7=7.69 Hz, 3H), 3.92 (br s, 2H), 4.27- 4.35 (m, 1H), 4.41 (d, 7=5.75 Hz, 2H), 5.05-5.13 (m, 3H), 6.33 (s, 1H), 7.09-7.13 (m, 2H), 7.43-7.51 (m, 4H), 7.66 (d, 7=8.63 Hz, 1H).
Example 4: Synthesis of (lR,3S)-3-(3-(2-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)acetamido)-lH-pyrazol-5-yl)cyclopentyl (2S)-2- methylazetidine-l-carboxylate (Compound P-12)
Figure imgf000112_0001
[0252] A solution of l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)pyrrolidine-3- carbaldehyde (250 mg, 703.54 pmol, 1 eq) [WO2020/38415 Al], tert-butyl 2-(4-piperidyl) acetate (168.25 mg, 844.25 pmol, 1.2 eq), NaOAc (57.71 mg, 703.54 pmol, 1 eq) and AcOH (42.25 mg, 703.54 pmol, 40.24 pL, 1 eq) in DMA (10 mL) was stirred at 50 °C for 2 hours. NaBHA’N (88.42 mg, 1.41 mmol, 2 eq) was added and the resulting solution was stirred for 12 hours at 50 °C. The mixture was quenched with water (0.1 mL). The mixture was purified by prep-HPLC [Phenomenex Luna Cis 200 x 40mm x 10 pm; 35 to 70%, 1% formic acid in water to ACN] and lyophilized to give tert-butyl 2-(l- (( 1 -(2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)pyrrolidin-3 -yl)methyl)piperidin-4- yl)acetate. ‘H NMR (400 MHz, d4-MeOD) 5 1.46 (s, 11 H), 1.80 - 1.96 (m, 4 H), 2.05 - 2.15 (m, 1 H), 2.18 - 2.35 (m, 3 H), 2.42 - 2.60 (m, 2 H), 2.61 - 2.97 (m, 6 H), 3.17 - 3.30 (m, 3 H), 3.41 - 3.51 (m, 1 H), 3.52 - 3.62 (m, 1 H), 3.64 - 3.76 (m, 1 H), 5.05 (dd, 7=12.52, 5.48 Hz, 1 H), 6.83 (dd, 7=8.46, 2.15 Hz, 1 H), 6.99 (d, 7=2.15 Hz, 1 H), 7.65 (d, 7=8.34 Hz, 1 H).
Step 2:
Figure imgf000112_0002
[0253] A solution of tert-butyl 2-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)acetate (70 mg, 4.24 mmol, 1 eq) in HCl/EtOAc (2 M, 5.83 mL, 89.77 eq) was stirred at 20 °C for 2 h. The mixture was concentrated under reduce pressure to give 2-( 1 -(( 1 -(2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)pyrrolidin-3 -yl)methyl)piperidin-4- yl)acetic acid which was used in the next step without further purification. rH NMR (400 MHz, d4- MeOD) 5 1.23 (t, J=6.97 Hz, 1 H), 1.59 (s, 1 H), 1.66 (br s, 2 H), 1.94 (br s, 1 H), 2.09 (br s, 4 H), 2.34 (br s, 2 H), 2.38 (br s, 1 H), 2.73 (br d, J=14.90 Hz, 2 H), 2.79 - 2.97 (m, 2 H), 3.07 (br d, J=1.55 Hz, 2 H), 3.49 (br d, J=2.50 Hz, 1 H), 3.56 - 3.64 (m, 1 H), 3.67 (br d, J=6.44 Hz, 2 H), 3.79 (br s, 1 H), 5.05 (br d, J=9.30 Hz, 1 H), 6.84 (br s, 1 H), 6.99 (br s, 1 H), 7.65 (br s, 1 H).
Step 3:
Figure imgf000113_0001
[0254] To a mixture of (lR,3S)-3-(3-amino-lH-pyrazol-5-yl)cyclopentyl (S)-2 -methylazetidine- 1- carboxylate (44.51 mg, 168.38 pmol, 1 eq), 2-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin- 5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)acetic acid (65 mg, 134.71 pmol, 0.8 eq) and T3P (535.76 mg, 841.92 pmol, 500.71 pL, 50% purity, 5 eq) in DCM (0.5 mL) was added DIEA (108.81 mg, 841.92 pmol, 146.64 pL, 5 eq). The mixture was stirred at 20 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC [Phenomenex Luna Cis 75 x 30mm x 3 pm; 20 to 60%, 1% formic acid in water to ACN] and lyophilized to give (1R,3S)-
3 -(3 -(2-( 1 -(( 1 -(2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)pyrrolidin-3 -yl)methyl)piperidin- 4-yl)acetamido)-lH-pyrazol-5-yl)cyclopentyl (2S)-2-methylazetidine-l -carboxylate. ’H NMR (400 MHz, d4-MeOD) 5 1.28 - 1.41 (m, 3 H), 1.49 - 1.68 (m, 2 H), 1.74 - 2.21 (m, 10 H), 2.29 - 2.43 (m, 2 H), 2.50 - 3.10 (m, 9 H), 3.18 - 3.25 (m, 1 H), 3.33 - 3.52 (m, 5 H), 3.55 - 3.64 (m, 1 H), 3.66 - 3.94 (m,
4 H), 4.26 - 4.39 (m, 1 H), 4.99 - 5.13 (m, 2 H), 5.86 (s, 1 H), 6.84 (dd, J=8.38, 2.00 Hz, 1 H), 7.00 (d, .7=2.00 Hz, 1 H), 7.66 (d, J=8.50 Hz, 1 H), 8.49 (br s, 1 H).
[0255] Additional compounds set forth in Table 3 were prepared following the procedures set forth above, with the exception that the amine was replaced in the example above with an amine depicted in the final product.
Table 3
Figure imgf000113_0002
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_0002
Example 5: Synthesis of N-{5-[(lS,3R)-3-(2-pyridyloxy)cyclopentyl]-3-pyrazolyl}p-{4-[2-(2,6- dioxo-3-piperidyl)-l,3-dioxo-5-isoindolinyl]-l-piperidyl}benzamide (Compound P-137)
Figure imgf000122_0001
Step 1:
Figure imgf000123_0001
[0256] To a solution of benzyl ( l -(tcrt-butyl)-5-(( I.S'.3/?)-3-hydroxycyclopcntyl)- l H-pyrazol-3- yl)carbamate (2 g, 5.60 mmol, 1 eq) and 2-fluoropyridine (1.09 g, 11.19 mmol, 961.49 pL, 2 eq) in DMSO (30 mb) was added KO'Bu (1.88 g, 16.79 mmol, 3 eq). The mixture was stirred at 25°C for 1 hour. Water (200 mL) was added and extracted into EtOAc (3 x 200 mL). The combined organic phases were washed with brine (200 mL), dried over Na2SC>4 and concentrated under reduced pressure to give benzyl (l-(tert-butyl)-5-((lS,37?)-3-(pyridin-2-yloxy)cyclopentyl)-lH-pyrazol-3-yl)carbamate.
Step 2:
Figure imgf000123_0002
[0257] To a solution of benzyl ( l-(tert-butyl)-5-(( I.S'.3/?)-3-(pyridin-2-yloxy)cyclopcntyl)- l H- pyrazol-3-yl)carbamate (5 g, 11.51 mmol, 1 eq) in MeOH (50 mL) and THE (50 mL) was added Pd/C (1 g, 10% Pd by wt.). The mixture was purged and degassed with hydrogen 3 times. The mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere (15 psi). The mixture was fdtered. The fdtrate was concentrated under reduced pressure to give l -(tcrt-butyl)-5-(( I.S'.3/?)-3-(pyridin-2- yloxy)cyclopentyl)- lH-pyrazol-3 -amine .
Step 3:
Figure imgf000123_0003
[0258] To a mixture of 4-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperidin-l- yl)benzoic acid (50 mg, 108.35 pmol, 1 eq) and l-(tert-butyl)-5-((lS,37?)-3-(pyridin-2- yloxy)cyclopentyl)-lH-pyrazol-3-amine (39.06 mg, 130.02 pmol, 1.2 eq) in pyridine (1 mL) was added EDCI (41.54 mg, 216.70 pmol, 2 eq). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to give the residue. The residue was diluted with water (3 mL) and extracted with ethyl acetate (3 x 1 mL). The combined organic phases were washed with brine (1 mb), dried over anhydrous Na2SC>4, filtered and concentrated to give N-( l-(tcrt-butyl)-5-(( I.S'.3/?)-3- (pyridin-2-yloxy)cyclopentyl)-lH-pyrazol-3-yl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)piperidin-l-yl)benzamide which was used in the following step without purification.
Step 4:
Figure imgf000124_0001
[0259] A solution ofN-(l-(tert-butyl)-5-((lS,37?)-3-(pyridin-2-yloxy)cyclopentyl)-lH-pyrazol-3-yl)- 4-(4-(2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)piperidin- 1 -yl)benzamide (80 mg, 107.55 pmol, 1 eq) in formic acid (1 mL) was stirred for 12 hours at 70 °C. The mixture was dried in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna Cis 80 mm x 30 mm x 3 gm; mobile phase: [LLO (+ 0.2% formic acid)-ACN]; gradient: 20%-60% B over 8.0 min) to give N-{5-[(lS,37?)-3-(2-pyridyloxy)cyclopentyl]-3-pyrazolyl}p-{4-[2-(2,6-dioxo-3-piperidyl)-l,3- dioxo-5-isoindolinyl]-l-piperidyl}benzamide. rH NMR (400 MHz, dg-DMSO) 5 1.70 - 1.98 (m, 7 H) 2.01 - 2.12 (m, 3 H) 2.57 - 2.68 (m, 3 H) 2.84 - 2.97 (m, 3 H) 3.00 - 3.08 (m, 1 H) 3.12 - 3.17 (m, 1 H) 4.05 (br d, 7=12.38 Hz, 2 H) 5.14 (dd, 7=12.94, 5.19 Hz, 1 H) 5.36 - 5.49 (m, 1 H) 6.36 - 6.49 (m, 1 H) 6.79 (d, 7=8.38 Hz, 1 H) 6.95 (dd, 7=6.57, 5.57 Hz, 1 H) 7.02 (br d, 7=8.88 Hz, 2 H) 7.64 - 7.72 (m, 1 H) 7.76 - 7.95 (m, 5 H) 8.16 (dd, 7=4.75, 1.50 Hz, 1 H) 10.26 - 10.49 (m, 1 H) 11.02 - 11.21 (m, 1 H) 11.93 - 12.32 (m, 1 H).
Example 6: Synthesis of N-{5-[(15,37?)-3-(2-pyridyloxy)cyclopentyl]-3-pyrazolyl}4-{l-[2-(2,6- dioxo-3-piperidyl)-l,3-dioxo-5-isoindolinyl]-4-piperidyl}-3-fluorobenzamide (Compound P-133)
Figure imgf000124_0002
Step 1:
Figure imgf000125_0001
[0260] To a solution of 4-bromo-3 -fluorobenzoic acid (20 g, 91.32 mmol, 1 eq) in CHCI3 (200 mL) was added 2-tert-butyl-l,3-diisopropyl-isourea (63.59 g, 182.64 mmol, 2 eq). The mixture was stirred at 40 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiCh, 10% ethyl acetate in petroleum ether) to give tert-butyl 4-bromo-3 -fluorobenzoate. 1HNMR (400 MHz, dg-DMSO) 5 1.53 (s, 9 H) 7.58 - 7.69 (m, 2
H) 7.74 - 7.84 (m, 1 H).
Step 2:
Figure imgf000125_0002
[0261] A mixture of tert-butyl 4-bromo-3 -fluorobenzoate (3 g, 10.90 mmol, 1 eq), tert-butyl 4- (4, 4, 5, 5 -tetramethyl- 1,3, 2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l -carboxylate (2.98 g, 16.36 mmol, 1.5 eq), Pd(dppf)C12 (796 mg, 1.09 pmol, 0.1 eq), K2CO3 (4.52 g, 32.71 mmol, 3 eq) in dioxane (30 mL) and H2O (15 mL) was degassed and purged with N2 three times. The mixture was stirred at 105 °C for 12 hours under a nitrogen atmosphere. H2O (10 mL) was added at 20°C, and then diluted with EtOAc (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, 10% ethyl acetate in petroleum ether) to give tert-butyl 4-(4-(tert-butoxycarbonyl)-2-fluorophenyl)-3,6-dihydropyridine- l(2H)-carboxylate. ’H NMR (400 MHz, CDCI3) 5 1.46 (s, 9 H) 1.55 (s, 9 H) 2.48 (br s, 2 H) 3.59 (br t, J=5.44 Hz, 2 H) 4.05 (br d, J=2.13 Hz, 2 H) 5.99 (br s, 1 H) 7.22 - 7.26 (m, 1 H) 7.60 (dd, J=\ 1.69, 1.56 Hz, 1 H) 7.69 (dd, J=8.00, 1.63 Hz, 1 H).
Step 3:
Figure imgf000125_0003
[0262] To a solution of tert-butyl 4-(4-(tert-butoxycarbonyl)-2-fluorophenyl)-3,6-dihydropyridine- 1(2H) -carboxylate (3.5 g, 9.27 mmol, 1 eq) in MeOH (70 mL) was added Pd/C (0.7 g, 10% wt% Pd) under a N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 20 °C for 12 hours. The mixture was fdtered and concentrated under reduced pressure to give tert-butyl 4-(4-(tert-butoxycarbonyl)-2-fluorophenyl)-3,6-dihydropyridine- l(2H)-carboxylate which was used in next step without further purification. rH NMR (400 MHz, CDCh) 5 1.53 (s, 9 H) 1.63 (s, 9 H) 1.66 - 1.71 (m, 2 H) 1.85 (br d, 7=12.26 Hz, 2 H) 2.88 (brt, 7=11.38 Hz, 2 H) 3.03 - 3.13 (m, 1 H) 4.31 (br s, 2 H) 7.28 - 7.32 (m, 1 H) 7.67 (dd, 7=11.01, 1.50 Hz, 1 H) 7.78 (br d, 7=8.00 Hz, 1 H).
Step 4:
Figure imgf000126_0001
[0263] A solution of tert-butyl 4-(4-(tert-butoxycarbonyl)-2-fluorophenyl)piperidine-l -carboxylate (3.4 g, 8.96 mmol, 1 eq) in TFA (10 mL) and DCM (30 mL) was stirred at 30 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-fluoro-4-(piperidin-4-yl)benzoic acid which was used in the next step without further purification. 1 H NMR (400 MHz, CDCh) 5 2.18 (br d, 7=6.50 Hz, 4 H) 3.18 - 3.33 (m, 3 H) 3.72 (br d, 7=13.26 Hz, 2 H) 7.38 (t, 7=7.57 Hz, 1 H) 7.81 (dd, 7=10.44, 1.31 Hz, 1 H) 7.94 (dd, 7=7.94, 1.19 Hz, 1 H).
Step 5:
Figure imgf000126_0002
[0264] To a solution of 3-fluoro-4-(piperidin-4-yl)benzoic acid (2 g, 8.96 mmol, 1.5 eq), 2-(2,6- dioxopiperidin-3-yl)-5-fluoroisoindoline-l, 3-dione (1.65 g, 5.97 mmol, 1.0 eq) in DMSO (20 mL) was added DIEA (1.54 g, 11.95 mmol, 2.08 mL, 2 eq). The mixture was stirred at 120 °C for 12 hours. The reaction was purified by prep-HPLC (column: Welch Xtimate Cis 180 mm x 70 mm x 10 pm; mobile phase: [H2O (+0.01%TFA)-ACN]; gradient: 35 %-65% B over 20.0 min) and lyophilized to give 4-( 1 -(2-(2,6-dioxopiperidin-3-yl)- 1 ,3 -dioxoisoindolin-5 -yl)piperidin-4-yl)-3 -fluorobenzoic acid. XH NMR (400 MHz, d6-DMSO) 5 1.70 - 1.82 (m, 2 H) 1.82 - 1.89 (m, 2 H) 1.97 - 2.06 (m, 1 H) 2.54 - 2.64 (m, 2 H) 2.83 - 2.95 (m, 1 H) 3.07 - 3.26 (m, 3 H) 4.21 (br d, 7=13.01 Hz, 2 H) 5.08 (dd, 7=12.88, 5.25 Hz, 1 H) 7.29 (dd, 7=8.57, 1.81 Hz, 1 H) 7.38 (s, 1 H) 7.46 (t, 7=7.75 Hz, 1 H) 7.59 - 7.65 (m, 1 H) 7.70 (dd, 7=16.32, 8.32 Hz, 2 H) 11.08 (s, 1 H). Step 6:
Figure imgf000127_0001
[0265] To a solution of l-(tert-butyl)-5-(( I.S'.3/?)-3-(pyridin-2-yloxy)cyclopcntyl)-l H-pyrazol-3- amine (37.59 mg, 125.14 pmol, 1.2 eq) in pyridine (1 mL) was added EDCI (39.98 mg, 208.57 pmol, 2 eq) and 4-( 1 -(2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)piperidin-4-yl)-3 -fluorobenzoic acid (0.05 g, 104.28 pmol, 1 eq). The mixture was stirred at 30 °C for 12 hours. H2O (2 mL) was added at 20 °C, and then diluted with ethyl acetate (1 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic layers were washed with saturated brine (3 x 2 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was used in the next step without further purification.
Figure imgf000127_0002
[0266] A solution of N-( l-(tcrt-butyl)-5-(( I.S'.3/?)-3-(pyridin-2-yloxy)cyclopcntyl)-I H-pyrazol-3-yl)- 4-( 1 -(2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)piperidin-4-yl)-3 -fluorobenzamidee (50 mg, 65.63 pmol, 1 eq) in formic acid (1 mL) was stirred for 12 hours at 70 °C. The mixture was dried in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna Cis 80 mm x 30 mm x 3 pm; mobile phase: [H2O (+ 0.2% formic acid)-ACN]; gradient: 20%-60% B over 8.0 min) to give N-{5-[(lS,37?)-3-(2-pyridyloxy)cyclopentyl]-3-pyrazolyl}4-{l-[2-(2,6-dioxo-3- piperidyl)-l,3-dioxo-5-isoindolinyl]-4-piperidyl}-3-fluorobenzamide. 1H NMR (400 MHz, dg-DMSO) 5 1.68 - 1.94 (m, 7 H) 1.97 - 2.13 (m, 3 H) 2.55 - 2.68 (m, 3 H) 2.84 - 2.94 (m, 1 H) 3.07 - 3.23 (m, 4 H) 4.23 (br d, J=\ 1.76 Hz, 2 H) 5.08 (br dd, 7=12.38, 5.25 Hz, 1 H) 5.42 (br s, 1 H) 6.47 (br s, 1 H) 6.78 (br d, 7=8.38 Hz, 1 H) 6.92 - 6.98 (m, 1 H) 7.28 - 7.34 (m, 1 H) 7.39 (br s, 1 H) 7.45 (br t, 7=7.25 Hz, 1 H) 7.63 - 7.72 (m, 2 H) 7.73 - 7.86 (m, 2 H) 8.13 - 8.19 (m, 1 H) 10.75 (br s, 1 H) 11.08 (br s, 1 H) 12.23 (br s, 1 H). [0267] Additional compounds set forth in Table 4 were prepared following the procedures set forth above, with the exception that the ether was replaced in the example above with an ether as depicted in the final product.
Table 4
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
[0268] In one embodiment the compounds disclosed herein preferably contain (lR,3S)-cyclopentyl or (lR,3S)-cyclopentyl; such preferred compounds would exclude compounds in Table 1 lacking (1R,3S)- cyclopentyl or (lR,3S)-cyclopentyl.
Biological Examples
Cereblon (CRBN) Target Engagement
[0269] HEK-293T cells were harvested ca. 75% confluent with trypsin and plated (500,000 cells/well) in a 6-well tissue culture plate in 2 m of Dulbecco’s Modified Eagle Medium (DMEM) + 10% Fetal Bovine Serum (FBS) and incubated overnight at 37 °C.
[0270] The NanoLuc-CRBN fusion vector (Nluc-CRBN; Promega) contains the coding region of human E3 ligase component cereblon (CRBN) fused to the C-terminus of the NanoLuc luciferase coding region. A mixture of 10 ng Nluc-CRBN and 990 ng DDB1 Expression Vector (Promega) was added to 125 pL Opti-Minimum Essential Medium (Opti-MEM™; Thermo Fisher) along with 2 pL P3000 reagent (Thermo Fisher) in a 1.5 mb epppendorf tube. This solution was added to Lipofectamine 3000 transfection reagent (5 pL; Thermo Fisher) in Opti-MEM (125 pL), mixed well, and incubated for 15 minutes at room temperature. The transfection mixture was added dropwise to cells and incubated overnight at 37 °C, 5% CO2. Following transfection, cells were washed once with PBS, and trypsin (250 pL) was added and incubated 30-45 sec to dislodge cells. Complete media (2 mL) was added to resuspend cells to form a single cell suspension. Cells were centrifuged at 320x g for 5 min at room temperature, the supernatant was removed, and the cell pellet resuspended in Opti-MEM (3 mL; wash step repeated x2). After final resuspension in 5 mL Opti-MEM, cells were counted and resuspended at 200,000 cells/mL in Opti-MEM.
[0271] Cereblon target engagement was monitored by Bioluminescence Resonance Energy Transfer (BRET) in transfected HEK-293T cells using the NanoBRET TE Intracellular E3 Ligase Assay (Promega). Briefly, 384-well plates (white opaque plates, Coming 3574, low binding surface) were seeded with transfected HEK-293T cells (38 pL/well). 2 pL of 10 pM CRBN tracer (diluted 1:5 in Tracer Dilution Buffer) was added to each well. Plates were centrifuged at 320x g for 1 min at room temperature. Test compounds were added in a 11 -point dilution series (typically 10 pM to 100 pM) using a TECAN D300e Digital Dispenser. Plates were shaken for 2 minutes on a microplate shaker to mix compounds. Plates were centrifuged at 320x g for 1 min at room temperature, and subsequently incubated for 2 hours at 37 °C.
[0272] After incubation, plates were allowed to cool to room temperature for 15 minutes. 20 pL of 3X Complete NanoBRET™ Nano-Gio® Substrate plus Inhibitor Solution (Promega, 1: 166 Substrate and 1:500 dilution of Extracellular NanoLuc® Inhibitor diluted in Opti-MEM) were added to each well. Plates were incubated with shaking at room temperature for 3 minutes covered with foil. Plates were read on a CLARIOstar microplate reader (BMG LabTech), measuring at 450nm (donor emission) and 610nm (acceptor emission). The IC50 values were determined by regression to best fit four-parameter logistic curves using GraphPad Prism.
CDK2 degradation assay
[0273] HiBiT- CDK2 HEK293T cells were harvested ca. 75% confluent with trypsin and plated (500,000 cells/well) in a 6-well tissue culture plate in 2 mL of Dulbecco’s Modified Eagle Medium (DMEM) + 10% Fetal Bovine Serum (FBS) and incubated overnight at 37 °C.
[0274] Representative compounds were evaluated for their ability to degrade CDK2 in the following assay. The CDK2 degradation assays were carried out by harvesting the HiBiT- CDK2 HEK293T reporter ceil lines and resuspending the cells in media formulated for reduced background fluorescence. The respective cell lines were seeded at a density of 4,000 cells/well into 384 well white opaque TC plates (Greiner 781080-20). The cells were incubated overnight to allow for attachment to the assayplate (37°C with humidified air and 5% CO2 for all incubations). Dilutions of the compounds were prepared in dimethyl sulfoxide (DMSO) from 10 mM compound stock solutions in DMSO. The assayplates were treated with appropriate concentrations of the compounds by dispensing the DMSO dilutions in quadruplicate wells with an upper limit of 0.5% final DMSO. After a 6-hour incubation with the compounds. HiBiT lytic buffer, 1: 100 LgBiT and 1:50 HiBiT were added at 30pl/welI, and plates were incubated at room temperature for 2 hours covered with foil. Images were acquired using the ClarioStar plate reader system (cells maintained at 37 °C during imaging). Cell Reporter Xpress software was utilized to segment cells and determine fluorescence intensities, which were used to construct dose-response curves and calculation of degradation DC50S (GraphPad Prism). The percent degradation amounts were calculated visually from the curves generated at a concentration of 1 and 10 micromolar.
CDK2 Target Engagement assay
[0275] HEK-293T cells were harvested ca. 75% confluent with trypsin and plated (500,000 cells/well) in a 6-well tissue culture plate in 2 mL of Dulbecco’s Modified Eagle Medium (DMEM) + 10% Fetal Bovine Serum (FBS) and incubated overnight at 37 °C.
[0276] A mixture of 10 ng NanoLuc-CDK2 and 990 ng CCNE1 Expression Vector (Promega) was added to 125 pL Opti-Minimum Essential Medium (Opti-MEM™; Thermo Fisher) along with 2 pL P3000 reagent (Thermo Fisher) in a 1.5 mL epppendorf tube. This solution was added to Lipofectamine 3000 transfection reagent (5 pL; Thermo Fisher) in Opti-MEM (125 pL), mixed well, and incubated for 15 minutes at room temperature. The transfection mixture was added dropwise to cells and incubated overnight at 37 °C, 5% CO2. Following transfection, cells were washed once with PBS (250 pL). Trypsin (250 pL) was added and incubated 30-45 sec to dislodge cells. Complete media (2 mL) was added to resuspend cells to form a single cell suspension. Cells were centrifuged at 320x g for 5 min at room temperature, the supernatant was removed, and the cell pellet resuspended in Opti-MEM (3 mL; wash step repeated x2). After final resuspension in 5 mL Opti-MEM, cells were counted and resuspended at 200,000 cells/mL in Opti-MEM + 1% FBS.
[0277] CDK2 target engagement was monitored by Bioluminescence Resonance Energy Transfer (BRET) in transfected HEK-293T cells using the NanoBRET Assay. Briefly, 384-well plates (white opaque plates, Coming 3574, low binding surface) were seeded with transfected HEK-293T cells (38 pL/well). 2 pL of 10 pM K-10 tracer (diluted 1:5 in Tracer Dilution Buffer) was added to each well. Plates were centrifuged at 320x g for 1 min at room temperature. Test compounds were added in a 10- point dilution series (typically 10 pMto 100 pM) using a TECAN D300e Digital Dispenser. Plates were shaken for 20 secondss on a microplate shaker to mix compounds. Plates were centrifuged at 320x g for 1 min at room temperature, and subsequently incubated for 2 hours at 37 °C.
[0278] After incubation, plates were allowed to cool to room temperature for 15 minutes. 20 pL of 3X Complete NanoBRET™ Nano-Gio® Substrate plus Inhibitor Solution (Promega, 1: 166 Substrate and 1:500 dilution of Extracellular NanoLuc® Inhibitor diluted in Opti-MEM) were added to each well. Plates were incubated with shaking at room temperature for 3 minutes covered with foil. Plates were read on a CLARIOstar microplate reader (BMG LabTech), measuring at 450nm (donor emission) and 610nm or 630 nm (acceptor emission). The IC50 values were determined by regression to best fit four- parameter logistic curves using GraphPad Prism.
[0279] Table 5 and Table 6 show results from the assays described above.
Table 5
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Table 6
Figure imgf000137_0001
Figure imgf000138_0001

Claims

What is claimed is:
1. A compound of formula I ’ :
Figure imgf000139_0001
r or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Y is N or C-V;
Ring C is
Figure imgf000139_0002
wherein the solid bond 1 attaches Ring C to Y and the solid bond 2 attaches Ring C to L;
V is selected from hydrogen, deuterium, and fluoro;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
R12 and R12 are independently selected from hydrogen, deuterium, and fluoro; or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R3 and R4 are independently hydrogen or CH3; or R3 and R4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
R13 is hydrogen or -CH2-OR14;
R14 is -C(O)-R15 or -P(O)(OR16)2;
R15 is C1-C4 alkyl or C1-C4 alkoxy; each R16 is independently hydrogen or C1-C4 alkyl;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5 -membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent; Y1 is -O- or -CH2-;
Z is -O- or -CH2-;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, I -(C3-Cg cycloalkyl), and L1-(4- to 7-membered heterocycloalkyl), wherein said Ci-Cg alkyl, C3-C6 cycloalkyl and 4- to 7- membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 11- membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N, N(R17), and S(O)m as a ring member, wherein said 3- to 11-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, C1-C4 alkyl, or C(O)-(Ci-C4 alkyl);
R18 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C(O)-(Ci-C4 alkyl); m is 0, 1 or 2;
L1 is a bond or a C1-C2 alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000140_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein Ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein Ring B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or Ring B is absent; a, b, and c are independently 0 or 1 ; each of W and W2, if present, is independently Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W, W1 and W2 is no more than 6; or when each of W and W2 are absent, then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms; and
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
2. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, wherein Ring
Figure imgf000141_0001
3. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 or claim 2, wherein Ring
Figure imgf000141_0002
4. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 or claim 2, wherein Ring
Figure imgf000141_0003
5. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, wherein Ring
Figure imgf000141_0004
6. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1 or claim 5, wherein Ring
Figure imgf000141_0005
7. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 5 or claim 6, wherein X is hydrogen or halo.
8. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein Ring D is a Cg-Cio aryl ring.
9. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein Ring D is a Cs-Cg cycloalkyl ring.
10. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein Ring D is a 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms.
11. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein Ring D is a 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms.
12. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein Ring D is absent.
13. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein Ring D is absent,
Figure imgf000142_0001
Figure imgf000142_0002
14. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-13, wherein Ring A is a 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms.
15. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of
Figure imgf000142_0003
16. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein a is zero in L which is then represented by formula Ila:
Figure imgf000143_0001
17. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein a and c are zero in L which is then represented by formula lib:
Figure imgf000143_0002
18. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-17, wherein B is a 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, -NR10Rn, and -C(O)NR10Rn.
19. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of
Figure imgf000143_0003
20. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of
Figure imgf000143_0004
Figure imgf000144_0001
21. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein a and c are zero and B is absent in L which is then represented by formula lie:
Figure imgf000144_0002
22. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 21, wherein b is 1 and W1 is O or C k
23. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of
Figure imgf000144_0003
24. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 21, wherein b is 0.
25. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 24, wherein
Figure imgf000145_0001
26. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-25, wherein n is 0.
27. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-25, wherein n is 1.
28. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-27, wherein p is 1.
29. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein R1 and R2 are independently selected from hydrogen and Ci-Cg alkyl.
30. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 11 -membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N, N(R17), and S(O)m as a ring member, wherein said 4- to 6-membered ring is optionally substituted by one to four R8.
31. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of
Figure imgf000145_0004
Figure imgf000145_0002
32. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-28, wherein -NR’ R2 is -NHCH( 043)2 or
Figure imgf000145_0003
33. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-32, wherein Z is -O-.
34. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-32, wherein Z is -CH2-.
35. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-34, wherein Y is C-V.
36. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 35, wherein V is hydrogen.
37. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-34, wherein Y is N.
38. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-37, wherein Y1 is -CH2-.
39. A compound of formula I:
Figure imgf000146_0001
I or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Ring C is
Figure imgf000146_0002
wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
V is selected from hydrogen, deuterium, and fluoro;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
R12 and R12 are independently selected from hydrogen, deuterium, and fluoro; or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R13 is hydrogen or -CH2-OR14;
R14 is C(O)-R15 or -P(O)(OR16)2;
R15 is C1-C4 alkyl or C1-C4 alkoxy; each R16 is independently hydrogen or C1-C4 alkyl;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5 -membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, L'-C’s-Cg cycloalkyl, and I -4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, C’s-Cg cycloalkyl and 4-7 membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 4- to 6- membered ring optionally containing an additional heteroatom selected from O, N, N(R17), and S(O)m as a ring member, wherein said 4- to 6-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl;
R18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
L1 is a bond or a C1-C2 alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000147_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; a, b, and c are independently 0 or 1 ; each of W and W2, if present, is independently Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W, W1 and W2 is no more than 6; or when each of W and W2 are absent, then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms; and
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
40. A compound of formula IA:
Figure imgf000148_0001
IA or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Ring
Figure imgf000148_0002
, wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
V is hydrogen;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
R12 and R12 are hydrogen, or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R13 is hydrogen;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4 to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6 to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 5-10 membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
Z is -O- or -CH2-; R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, I -(C3-Cg cycloalkyl), and L1-(4- to 7-membered heterocycloalkyl), wherein said Ci-Cg alkyl, C’s-Cg cycloalkyl and 4- to 7- membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 11- membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N(R17), and S(O)m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl;
R18 is hydrogen, C1-C4 alkyl, C1-4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
L1 is a bond or a C1-C2 alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000149_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to
10-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to
11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; b and c are independently 0 or 1 ;
W2, if present, is Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W1 and W2 is no more than 4; and
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy; or when W is absent then W1 is C4-C8 heteroalkylene containing 1 to 3 oxygen atoms.
41. A compound of formula IB:
Figure imgf000150_0001
IB or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Ring
Figure imgf000150_0002
wherein the solid bond 1 attaches Ring C to the piperidinedione ring and the solid bond 2 attaches Ring C to L;
V is hydrogen;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy;
R12 and R12 are hydrogen, or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R13 is hydrogen;
Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 5-10 membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
Z is -O- or -CH2-;
R1 and R2 are independently selected from hydrogen, Ci-Cg alkyl, L'-G-Cg cycloalkyl, and L1-4-7 membered heterocycloalkyl, wherein said Ci-Cg alkyl, C -Cg cycloalkyl and 4- to 7-membered heterocycloalkyl is optionally substituted by one to four R8;
R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 11 -membered ring optionally containing an additional heteroatom or heteroatom group selected from O, N(R17), and S(O)m as a ring member, wherein said 3- to 6-membered ring is optionally substituted by one to four R8;
R17 is hydrogen, C1-C4 alkyl, or C(O)-Ci-C4 alkyl;
R18 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C(O)-Ci-C4 alkyl; m is 0, 1 or 2;
L1 is a bond or a C1-C2 alkylene optionally substituted with one to four R9;
L is represented by the formula:
Figure imgf000151_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-C6 cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to
10-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to
11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; b and c are independently 0 or 1 ;
W2, if present, is Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W1 and W2 is no more than 4;
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy; and when W2 is absent then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms.
42. A compound of formula III:
Figure imgf000152_0001
III or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein
Y is N or C-V;
Ring C is
Figure imgf000152_0002
wherein the solid bond 1 attaches Ring C to Y and the solid bond 2 attaches Ring C to L;
V is selected from hydrogen, deuterium, and fluoro;
X is selected from hydrogen, halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and Ci-4fluoroalkyloxy;
R12 and R12 are independently selected from hydrogen, deuterium, and fluoro; or R12 and R12 together are oxo; n is 0 or 1; p is 0 or 1;
R3 and R4 are independently hydrogen, halo, or CH3; or R3 and R4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
Y1 is -O- or -CH2-;
Z1 is -O-, and R5 is selected from Cg-Cio aryl; 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms; C3-C6 cycloalkyl ring; and C1-C3 alkyl optionally substituted with C1-C3 alkoxy or phenyl; wherein the Cg-Cio aryl and the 6-membered heteroaryl ring are substituted with 0 to 2 R6, and each R6 is independently selected from halo, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyl; or -Z^R5 is hydrogen;
R13 is hydrogen or -CH2-OR14;
R14 is C(O)-R15 or -P(O)(OR16)2;
R15 is C1-C4 alkyl or C1-C4 alkoxy; each R16 is independently hydrogen or C1-C4 alkyl; Ring D is selected from Cg-Cio aryl ring, Cs-Cg cycloalkyl ring, 4- to 5-membered heterocycloalkyl ring with 1 ring nitrogen atom, 6- to 7-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, or is absent;
R18 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C(O)-Ci-C4 alkyl;
L is represented by the formula:
Figure imgf000153_0001
wherein:
Ring A is selected from Cg-Cio aryl ring; C4-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6-membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein ring A is substituted with from 0 to 3 R7 moieties, and each R7 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn;
R10 and R11 are each independently H or C1-C4 alkyl;
Ring B is selected from Cg-Cio aryl; Cs-Cg cycloalkyl ring; Cs-Cg cycloalkenyl ring; 5- to 6- membered heteroaryl ring with 1 to 3 ring heteroatoms independently selected from N, S, and O; 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms; and 4- to 11 -membered heterocycloalkenyl ring with 1 or 2 ring nitrogen atoms, wherein B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkyloxy, NR10Rn, and -C(O)NR10Rn, or B is absent; a, b, and c are independently 0 or 1 ; each of W and W2, if present, is independently Ci-Cg alkylene optionally substituted with 1 to 3 R9 and W1, if present, is -C(O)-, O, S, NR18 or Ci-Cg alkylene optionally substituted with 1 to 3 R9 provided that the aggregate sum of carbon atoms in W, W1 and W2 is no more than 6; or when each of W and W2 are absent, then W1 further comprises C4-C8 heteroalkylene containing 1 to 3 oxygen atoms; and
R9 is independently selected from halo, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, and C1-C4 fluoroalkyloxy.
43. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42, wherein Ring
Figure imgf000153_0002
44. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42, wherein Ring
Figure imgf000154_0001
45. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42, wherein Ring
Figure imgf000154_0002
46. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 42, wherein X is fluoro.
47. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-46, wherein Ring D is a Cg-Cio aryl ring.
48. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-46, wherein Ring D is absent.
49. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-46, wherein Ring D is absent or
Figure imgf000154_0003
50. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-49, wherein Ring A is a 4- to 11 -membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms.
51. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 50, wherein Ring
Figure imgf000154_0004
52. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-51, wherein a is zero in L which is then represented by formula Ila:
Figure imgf000155_0001
53. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-51, wherein a and c are zero in L which is then represented by formula lib:
Figure imgf000155_0002
54. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-53, wherein B is a 4- to 11-membered heterocycloalkyl ring with 1 or 2 ring nitrogen atoms, and B is substituted with from 0 to 3 R8 moieties, wherein each R8 is independently selected from halo, hydroxy, cyano, CM alkyl, CM fluoroalkyl, C alkoxy, CMfhioroalkyloxy, -NR10Rn, and -C(O)NR10Rn.
55. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 54, wherein
Figure imgf000155_0003
56. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 54 or claim 55, wherein L is
Figure imgf000155_0004
57. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-53, wherein a and c are zero and B is absent in L which is then represented by formula lie:
Figure imgf000155_0005
58. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 57, wherein b is 1 and W1 is -CH2-.
59. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 58, wherein
Figure imgf000156_0001
60. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 57, wherein b is 0.
61. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 60, wherein
Figure imgf000156_0002
62. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-61, wherein n is 0.
63. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-61, wherein n is 1.
64. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-63, wherein p is 1.
65. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-64, wherein R5 is Cg-Cio aryl substituted with 0 to 2 R6.
66. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of
Figure imgf000156_0003
67. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-64, wherein R5 is 6-membered heteroaryl ring with 1 or 2 ring nitrogen atoms, and the 6-membered heteroaryl ring is substituted with 0 to 2 R6.
68. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of
Figure imgf000157_0003
69. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-64, wherein R5 is C1-C3 alkyl optionally substituted with C1-C3 alkoxy or phenyl.
70. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 69, wherein
Figure imgf000157_0001
71. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-64, wherein R5 is a C3-C6 cycloalkyl ring.
72. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 71, wherein
Figure imgf000157_0002
73. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-72, wherein -Z^R5 is hydrogen.
74. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-73, wherein Y is C-V.
75. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 74, wherein V is hydrogen.
76. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-73, wherein Y is N.
77. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 42-76, wherein Y1 is -CH2-.
78. A compound selected from Table 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
79. A compound selected from Table 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
80. A pharmaceutical composition comprising a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79 and a pharmaceutically acceptable excipient.
81. A method for treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part, by CDK2, or a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79 or a pharmaceutical composition of claim 80.
82. The method of claim 81, wherein the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2, is one or more selected from liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma.
83. The method of claim 81, wherein the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2, is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma.
84. The method of claim 81, wherein the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2, is selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gramnegative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.
85. The method of any one of claims 81-84, further comprising administering to the subject one or more additional therapies or therapeutic agents.
86. The method of claim 85, wherein the one or more additional therapies or therapeutic agents are selected from surgery, radiotherapy, endocrine therapy, biologic response modifiers, hyperthermia and cryotherapy, agents to attenuate any adverse effects, alkylating drugs, antimetabolites, purine antagonists and pyrimidine antagonists, spindle poisons, podophyllotoxins, antibiotics, nitrosoureas, inorganic ions, enzymes, and hormones.
87. A compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79 or a pharmaceutical composition of claim 80, for use in treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part by, CDK2, or a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2.
88. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof or composition for use of claim 87, wherein the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2, is one or more selected from liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma.
89. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof or composition for use of claim 87, wherein the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2, is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma.
90. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof or composition for use of claim 87, wherein the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2, is one or more selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gramnegative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.
91. Use of a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-79 or a pharmaceutical composition of claim 80, in the preparation of a medicament for treating a CDK2 dependent disease or disorder or a disease or disorder that is mediated, at least in part by, CDK2, or a disease characterized by amplification or overexpression of cyclin El (CCNE1) or cyclin E2 (CCNE2) or both CCNE1 and CCNE2.
92. The use of claim 91, wherein the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2, is one or more selected from liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, and diffuse large B-cell lymphoma.
93. The use of claim 91, wherein the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2, is one or more selected from prostate cancer, breast carcinoma, lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma.
94. The use of claim 91, wherein the CDK2 dependent disease or disorder or the disease or disorder that is mediated, at least in part by, CDK2, is one or more selected from rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gramnegative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.
95. A method for modulating or degrading CDK2, comprising contacting CDK2 with a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1- 79 or a pharmaceutical composition of claim 80.
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