WO2023168686A1 - Cyclopentanes substitués utilisés en tant qu'inhibiteurs de cdk2 - Google Patents

Cyclopentanes substitués utilisés en tant qu'inhibiteurs de cdk2 Download PDF

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WO2023168686A1
WO2023168686A1 PCT/CN2022/080313 CN2022080313W WO2023168686A1 WO 2023168686 A1 WO2023168686 A1 WO 2023168686A1 CN 2022080313 W CN2022080313 W CN 2022080313W WO 2023168686 A1 WO2023168686 A1 WO 2023168686A1
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compound
membered
pharmaceutically acceptable
stereoisomer
alkyl
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PCT/CN2022/080313
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English (en)
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Hailong Li
Hu HE
Wenge Zhong
Yuanhao WANG
Xiumei Chen
Wei Huang
Xianqiang SUN
Yang Yu
Junhong HUANG
Wei Liu
Xinde CHEN
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Qilu Regor Therapeutics Inc.
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Priority to PCT/CN2022/080313 priority Critical patent/WO2023168686A1/fr
Priority to PCT/CN2022/141421 priority patent/WO2023116884A1/fr
Priority to TW111149800A priority patent/TW202341982A/zh
Publication of WO2023168686A1 publication Critical patent/WO2023168686A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • CDKs Cyclin-Dependent Kinases
  • CDKs are relatively small proteins with molecular weights between about 34-40 kDa. They contain little more than the kinase domain, and are essentially inactive when not in complex with a class of regulatory proteins called cyclins. CDK levels remain relatively constant throughout the cell cycle, and most regulation is post-translational, most prominently by binding to cyclins.
  • CDK2 is of particular interest because deregulation of CDK2 activity occurs frequently in a variety of human cancers.
  • CDK2 plays a crucial role in promoting G1/Stransition and S phase progression.
  • CCNE cyclin E
  • CDK2 phosphorylates retinoblastoma pocket protein family members (p107, p130, pRb) , leading to de-repression of E2F transcription factors, expression of G1/Stransition related genes and transition from G1 to S phase (Henley, S.A. and F.A. Dick, Cell Div, 2012, 7 (1) : 10) .
  • CDK2/cyclin A which phosphorylates endogenous substrates that permit DNA synthesis, replication and centrosome duplication. It has been reported that the CDK2 pathway influences tumorigenesis mainly through amplification and/or overexpression of CCNE1 and mutations that inactivate CDK2 endogenous inhibitors (e.g., p27) , respectively (Xu, X., et al., Biochemistry, 1999, 38 (27) : 8713-22) .
  • CCNE1 copy-number gain and overexpression have been identified in ovarian, gastric, endometrial, breast and other cancers and been associated with poor outcomes in these tumors (Keyomarsi, K., et al., N Engl J Med, 2002, 347 (20) : 1566-75; Nakayama, N., et al., Cancer, 2010, 116 (11) : 2621-34; Au-Yeung, G., et al., Clin Cancer Res, 2017, 23 (7) : 1862-1874; Rosen, D.G., et al., Cancer, 2006, 106 (9) : 1925-32) .
  • Amplification and/or overexpression of CCNE1 also reportedly contribute to trastuzumab resistance in HER2+breast cancer and resistance to CDK4/6 inhibitors in estrogen receptor-positive breast cancer (Scaltriti, M., et al., Proc Natl Acad Sci USA, 2011, 108 (9) : 3761-6; Herrera-Abreu, M.T., et al., Cancer Res, 2016, 76 (8) : 2301-13) .
  • CDK2 Various approaches targeting CDK2 have been shown to induce cell cycle arrest and tumor growth inhibition (Chen, Y N., et al., Proc Natl Acad Sci USA, 1999, 96 (8) : 4325-9; Mendoza, N., et al., Cancer Res, 2003, 63 (5) : 1020-4) . Inhibition of CDK2 also reportedly restores sensitivity to trastuzumab treatment in resistant HER2+ breast tumors in a preclinical model (Scaltriti, supra) .
  • CDK2 CDK1
  • CDK1 CDK1
  • CDK inhibitors having novel activity profiles, in particular those specifically or selectively targeting CDK2.
  • Described herein are compounds of Formula (I) that inhibit (e.g., selectively inhibit) the activity of CDK2, and pharmaceutically acceptable salts, or stereoisomers thereof.
  • the present disclosure provides a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof:
  • compositions comprising a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure further provides methods of inhibiting CDK2 in a patient, comprising administering to the patient a compound of Formula (I) , or a pharmaceutically acceptable salt, or a stereoisomer thereof.
  • the present disclosure also provides methods of treating a disease or condition modulated at least in part by CDK2 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof.
  • the present disclosure further provides a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of (1) a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof; or (2) a pharmaceutically acceptable composition comprising a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the cancer is treatable by inhibiting (e.g., selectively inhibiting) CDK2, such as a cancer selected from the group consisting of: ovarian cancer, breast cancer (such as hormone receptor positive, HER2/neu negative advanced or metastatic breast cancer, HER2 positive breast cancer and triple negative breast cancer ) , lung cancer, endometrial cancer, neuroblastoma, gastric cancer, colorectal cancer, prostate cancer, glioblastoma, melanoma, mantel cell lymphoma, chronic myeloid leukemia and acute myeloid leukemia.
  • CDK2 such as a cancer selected from the group consisting of: ovarian cancer, breast cancer (such as hormone receptor positive, HER2/neu negative advanced or metastatic breast cancer, HER2 positive breast cancer and triple negative breast cancer )
  • lung cancer endometrial cancer
  • neuroblastoma gastric cancer
  • colorectal cancer colorectal cancer
  • prostate cancer glioblastoma, melanoma
  • the cancer exhibits abnormally up-regulated CCNE1/Cyclin E activity, through overexpression of Cyclin Eor duplication of the Cyclin E-coding CCNE1 gene. In certain embodiments, the cancer exhibits abnormally up-regulated Cyclin A2 activity.
  • the cancer can be treated by inhibiting (e.g., selectively inhibiting) the activity of CDK2.
  • the compounds of the invention are administered with any one of a second therapeutic agent as described herein that also treats the same cancer.
  • the present disclosure also provides a use of a compound of Formula (I) , a pharmaceutically acceptable salt, or a stereoisomer thereof or a pharmaceutical composition comprising the same in any of the methods described herein.
  • a compound of Formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof or a pharmaceutical composition comprising the same for use in any of the methods described herein.
  • a compound of Formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof or a pharmaceutical composition comprising the same for the manufacture of a medicament for any of the methods described herein.
  • ring A is heteroaryl represented by
  • W is 3-12 membered heterocyclyl, or 5-10 membered heteroaryl; wherein said 3-12 membered heterocyclyl or 5-10 membered heteroaryl represented by W is optionally substituted by one or more halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
  • R 1 is H or C 1-6 alkyl; wherein said C 1-6 alkyl represented by R 1 is optionally substituted with one or more halogen, -OH, CN, oxo, or –NH 2 ;
  • R 1' is H, C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl represented by R 1' is optionally substituted with one or more halogen, CN, oxo, or C 1-6 alkyl;
  • R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxylalkyl, C 1-6 alkoxylC 1-6 alkylene, – (CH 2 ) 0 or 1 -3-12 membered carbocyclyl, – (CH 2 ) 0 or 1 -3-12 membered heterocyclyl, – (CH 2 ) 0 or 1 -6-10 membered aryl, or – (CH 2 ) 0 or 1 -5-10 membered heteroaryl; wherein said C 2-6 alkenyl, C 2-6 alkynyl, – (CH 2 ) 0 or 1 -3-12 membered carbocyclyl, – (CH 2 ) 0 or 1 -3-12 membered heterocyclyl, – (CH 2 ) 0 or 1 -6-10 membered aryl, or – (CH 2 ) 0 or 1 -5-10 membere
  • R 1 and R 2 together with the attached N atom, form a 3-8 membered heterocyclyl; wherein said 3-8 membered heterocyclyl is optionally substituted by one or more R # ; wherein each R # is independently F, hydroxyl, C 1-4 alkyl, C 1-4 alkoxyl, or CN;
  • R 3 is H or halogen
  • R 5 is H, halogen, C 1-6 alkyl, C (O) OR 5a , C (O) NR 5a R 5b , or
  • R 6 is H, halogen, or C 1-6 alkyl
  • each ring B is independently 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • U is a bond, -CH 2 -, -C ⁇ C-, or –C (O) NH-;
  • R 5a and R 5b are independently H or C 1-6 alkyl
  • each R 4a or R 5c is independently halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 alkoxylC 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, -C (O) R * , -C (O) OR * , -C (O) NR * R * , -OR * , -SO 2 R * , -NR * R * , -NR * C (O) R * , -NR * C (O) OR * , -NR * SO 2 R * , -NR * SO 2 NR * R * , -P (O) R * R * , 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein
  • said 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl represented by R 4a or R 5c is optionally substituted by one or more halogen or C 1-6 alkyl;
  • each R * is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered carbocyclyl, and 4-6 membered heterocyclyl;
  • n 0, 1, 2, 3, 4, or 5 (as appropriate) ;
  • n 0, 1, 2, 3, 4, or 5 (as appropriate) ;
  • R 7 is H or halogen
  • heterocyclyl comprises 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur; and said heteroaryl comprises 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur.
  • the present disclosure provides a compound according to the first embodiment, wherein the compound is represented by Formula IIA:
  • the present disclosure provides a compound according to the first embodiment, wherein the compound is represented by Formula IIB:
  • the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is selected from the group consisting of:
  • the present disclosure provides a compound according to any one of the first through fourth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is
  • ring A is The definitions of the remaining variables are provided in any one of the first through fourth embodiments.
  • the present disclosure provides a compound according to any one of the first through fourth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is The definitions of the remaining variables are provided in any one of the first through fourth embodiments.
  • the present disclosure provides a compound according to any one of the first through fourth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is The definitions of the remaining variables are provided in any one of the first through fourth embodiments.
  • the present disclosure provides a compound according to any one of the first through seventh embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein W is The definitions of the remaining variables are provided in any one of the first through seventh embodiments.
  • the present disclosure provides a compound according to any one of the first through eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein W is 5-10 membered heteroaryl optionally substituted by 1 to 3 C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, or C 2-4 alkynyl.
  • W is 5-10 membered heteroaryl optionally substituted by 1 to 3 C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, or C 2-4 alkynyl.
  • the definitions of the remaining variables are provided in any one of the first through eighth embodiments.
  • the present disclosure provides a compound according to the ninth embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein W is 5-6 membered heteroaryl (e.g. pyridinyl, pyrimidinyl) optionally substituted by C 1-4 alkyl (e.g., isopropyl) or C 2-4 alkenyl (e.g., isopropenyl) .
  • W is 5-6 membered heteroaryl (e.g. pyridinyl, pyrimidinyl) optionally substituted by C 1-4 alkyl (e.g., isopropyl) or C 2-4 alkenyl (e.g., isopropenyl) .
  • C 1-4 alkyl e.g., isopropyl
  • C 2-4 alkenyl e.g., isopropenyl
  • the present disclosure provides a compound according to any one of the first through eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 1 is H.
  • R 1 is H.
  • the definitions of the remaining variables are provided in any one of the first through eighth embodiments.
  • the present disclosure provides a compound according to any one of the first through eighth and eleventh embodiments, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-6 hydroxylalkyl, C 1-6 alkoxylC 1-6 alkylene, – (CH 2 ) 0 or 1 -3-6 membered carbocyclyl, – (CH 2 ) 0 or 1 -3-6 membered heterocyclyl, – (CH 2 ) 0 or 1 -phenyl, or – (CH 2 ) 0 or 1 -5-6 membered heteroaryl; wherein said C 2-4 alkenyl, C 2-4 alkynyl, – (CH 2 ) 0 or 1 -3-6 membered carbocyclyl, – (CH 2 ) 0 or 1 -3-6
  • the present disclosure provides a compound according to any one of the first through eighth, eleventh, and twelfth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 2 is H, C 1-5 alkyl, C 1-5 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 alkoxylC 1-4 alkylene, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, or - (CH 2 ) -phenyl; wherein said 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, or - (CH 2 ) -phenyl represented by R 2 is optionally substituted by one or two groups selected from halogen, hydroxyl, CN, and C 1-4 alkyl.
  • the definitions of the remaining variables are provided in any one of the first through eighth, eleventh, and twelfth embodiments.
  • the present disclosure provides a compound according to any one of the first through eighth and eleventh through thirteen embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 2 is C 1-4 alkyl, C 1-4 hydroxylalkyl, or cyclopropyl; wherein said cyclopropyl represented by R 2 is optionally substituted by C 1-2 alkyl.
  • R 2 is C 1-4 alkyl, C 1-4 hydroxylalkyl, or cyclopropyl
  • said cyclopropyl represented by R 2 is optionally substituted by C 1-2 alkyl.
  • the present disclosure provides a compound according to any one of the first through eighth and eleventh through thirteenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 2 is selected from the group consisting of:
  • the present disclosure provides a compound according to any one of the first through eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 1 and R 2 , together with the attached N, form a 4-6 membered heterocyclyl; wherein said 4-6 membered heterocyclyl is optionally substituted by one to three halogen (e.g. F) or C 1-4 alkyl.
  • halogen e.g. F
  • the present disclosure provides a compound according to any one of the first through eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 1 and R 2 , together with the attached N, form a pyrrolidinyl group.
  • R 1 and R 2 together with the attached N, form a pyrrolidinyl group.
  • the definitions of the remaining variables are provided in any one of the first through eighth embodiments.
  • the present disclosure provides a compound according to any one of the first through fifth and eighth through seventeenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 3 is H or F.
  • R 3 is H or F.
  • the definitions of the remaining variables are provided in any one of the first through fifth and eighth through seventeenth embodiments.
  • the present disclosure provides a compound according to any one of the first through fifth and eighth through eighteenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 3 is H.
  • R 3 is H.
  • the definitions of the remaining variables are provided in any one of the first through fifth and eighth through eighteenth embodiments.
  • the present disclosure provides a compound according to any one of the first through fourth and sixth through seventeenth embodiments, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 5 is H, halogen, CH 3 , isopropyl, C (O) OH, C (O) N (CH 3 ) 2 , or
  • R 5 is H, halogen, CH 3 , isopropyl, C (O) OH, C (O) N (CH 3 ) 2 , or
  • the definitions of the remaining variables are provided in any one of the first through fourth and sixth through seventeenth embodiments.
  • the present disclosure provides a compound according to any one of the first through fourth, sixth through seventeenth, and twentieth embodiments, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 5 is The definitions of the remaining variables are provided in any one of the first through fourth, sixth through seventeenth, and twentieth embodiments.
  • the present disclosure provides a compound according to any one of the first through fourth, sixth through seventeenth, twentieth, and twenty-first embodiments, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein U is a bond.
  • the definitions of the remaining variables are provided in any one of the first through fourth, sixth through sixteenth, eighteenth, and nineteenth embodiments.
  • the present disclosure provides a compound according to any one of the first through twenty-second embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • each ring B is independently 3-8 membered carbocyclyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl;
  • each R 4a or R 5c is independently halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 alkoxylC 1-4 alkylene, C 2-4 alkenyl, C 2-6 alkynyl, -OR * , -SO 2 R * , -C (O) NR * R * , -NR * SO 2 NR * R * , -C (O) R * , -C (O) OR * , -P (O) R * R * , phenyl, or 5-6 membered heteroaryl; wherein
  • said phenyl or 5-6 membered heteroaryl represented by R 4a or R 5c is optionally substituted by one to three halogen or C 1-4 alkyl;
  • each R * is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 4-6 membered carbocyclyl, and 5-6 membered heterocyclyl;
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3.
  • the present disclosure provides a compound according to any one of the first through twentieth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • each ring B is independently 4-6 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, phenyl, or 5-10 membered heteroaryl;
  • each R 4a or R 5c is independently halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 1-4 alkyleneC 1-2 alkoxy, -OR * , -SO 2 R * , -C (O) NR * R * , C (O) OR * , -P (O) R * R * , phenyl, or 5-6 membered heteroaryl; wherein
  • said phenyl or 5-6 membered heteroaryl represented by R 4a or R 5c is optionally substituted by one to two halogen or C 1-2 alkyl;
  • each R * is independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
  • n 0, 1, or 2;
  • n 0, 1, or 2.
  • the present disclosure provides a compound according to the twenty-second embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • ring B represented in the group of R 4 is 5-6 membered monocyclic heterocyclyl, phenyl, or 5-9 membered heteroaryl;
  • each R 4a is F, -CN, -OH, C 1-3 alkyl, C 1-2 hydroxylalkyl, -C 1-2 alkyleneC 1- 2 alkoxy, -OC 1-2 alkyl, -SO 2 C 1-2 alkyl, -C (O) NR * R * , C (O) OR * , -P (O) R * R * , phenyl, or 5-6 membered heteroaryl; wherein
  • said phenyl or 5-6 membered heteroaryl represented by R 4a is optionally substituted by halogen or C 1-2 alkyl;
  • each R * is independently selected from the group consisting of hydrogen or C 1-3 alkyl
  • n 0, 1, or 2.
  • the present disclosure provides a compound according to the twenty-fourth or twenty-fifth embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • ring B represented in the group of R 4 is 6 membered heteroaryl
  • each R 4a is C 1-2 hydroxylalkyl
  • m 0 or 1.
  • the present disclosure provides a compound according to any one of the first through twenty-fifth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring B represented in the group of R 4 is selected from the group consisting of
  • the present disclosure provides a compound according to any one of the first through fifth, eighth through twenty-fifth, and twenty-seventh embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 4a is selected from the group consisting of
  • the present disclosure provides a compound according to the twenty-fourth embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • ring B represented in the group of R 5 is 5-6 membered monocyclic carbocyclyl, 5-6 membered monocyclic heterocyclyl, phenyl, or 5-9 membered heteroaryl;
  • each R 5c is halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-2 alkoxylC 1-2 alkylene, -SO 2 C 1-3 alkyl, or -SO 2 C 1-3 haloalkyl;
  • n 0, 1, or 2.
  • the present disclosure provides a compound according to the first through twenty-ninth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring B represented in the group of R 5 is selected from the group consisting of
  • the present disclosure provides a compound according to the first through thirtieth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 5c is selected from the group consisting of
  • the present disclosure provides a compound according to the first through seventh and eighteenth through thirty first embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 1' is H or C 1-4 alkyl (e.g., isopropyl) .
  • R 1' is H or C 1-4 alkyl (e.g., isopropyl) .
  • the definitions of the remaining variables are provided in the the first through seventh and eighteenth through thirty-first embodiments.
  • the present disclosure provides a compound selected from the compounds disclosed in examples and Table 1, a pharmaceutically acceptable salt or a stereoisomer thereof.
  • halogen refers to fluoride, chloride, bromide, or iodide.
  • alkyl used alone or as part of a larger moiety, such as “alkoxy” or “haloalkyl” and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical of formula -C n H (2n+1) .
  • an alkyl group typically has 1-6 carbon atoms, i.e. C 1-6 alkyl.
  • a “C 1-6 alkyl” group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement.
  • Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, and the like.
  • haloalkyl means alkyl, as the case may be, substituted with one or more halogen atoms. In one embodiment, the alkyl can be substituted by one to three halogens. Examples of haloalkyl, include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl and the like.
  • alkylene as used herein, means a straight or branched chain divalent hydrocarbon group of formula -C n H 2n -. Non-limiting examples include ethylene, and propylene.
  • haloalkylene means alkylene, as the case may be, substituted with one or more halogen atoms. In one embodiment, the alkylene can be substituted by one to three halogens.
  • alkenyl means an alkyl group in which one or more carbon/carbon single bond is replaced by a double bond.
  • alkynyl means an alkyl group in which one or more carbon/carbon single bond is replaced by a triple bond.
  • carbocyclyl refers to any stable non-aromatic hydrocarbon ring having 3-12 membered carbocyclyl.
  • carbocyclyl is 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, or unsaturated.
  • Any substitutable ring atom can be substituted (e.g., by one or more substituents) .
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl.
  • carbocyclyl is intended to include, bridged, fused, and spirocyclic rings. In a spirocyclic carbocyclyl, one atom is common to two different rings.
  • spirocyclic carbocyclyl is spiro [3.3] heptanyl.
  • the rings share at least two common non-adjacent atoms.
  • bridged carbocyclyls include bicyclo [2.2.1] heptanyl, bicyclo [2.2.1] hept-2-enyl, and adamantanyl.
  • fused-ring carbocyclyl system two or more rings may be fused together, such that two rings share one common bond.
  • Examples of two-or three-fused ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl) , indenyl, indanyl (dihydroindenyl) , anthracenyl, phenanthrenyl, and decalinyl.
  • cycloalkyl refers to a cyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon groups having 3 to 12 ring carbons. In one embodiment, cycloalkyl may have 3 to 7 ring cabons. Any substitutable ring atom can be substituted (e.g., by one or more substituents) .
  • Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings.
  • Non-limiting examples of fused/bridged cycloalkyl include: bicyclo [1.1.0] butane, bicyclo [2.1.0] pentane, bicyclo [1.1.0] pentane, bicyclo [3.1.0] hexane, bicyclo [2.1.1] hexane, bicyclo [3.2.0] heptane, bicyclo [4.1.0] heptane, bicyclo [2.2.1] heptane, bicyclo [3.1.1] heptane, bicyclo [4.2.0] octane, bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, and the like.
  • Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom) .
  • spirocyclic cycloalkyls include spiro [2.2] pentane, spiro [2.5] octane, spiro [3.5] nonane, spiro [3.5] nonane, spiro [3.5] nonane, spiro [4.4] nonane, spiro [2.6] nonane, spiro [4.5] decane, spiro [3.6] decane, spiro [5.5] undecane, and the like.
  • heterocyclyl refers to a radical of a 3-to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO) , oxygen, and sulfur, including sulfoxide and sulfone ( “3-12 membered heterocyclyl” ) .
  • a heterocyclyl group is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “3-7 membered heterocyclyl” ) .
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ( “monocyclic heterocyclyl” ) or polycyclic (e.g., a bicyclic system ( “bicyclic heterocyclyl” ) or tricyclic system ( “tricyclic heterocyclyl” ) ; polycyclic ring systems include fused, bridged, or spiro ring systems) .
  • Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like.
  • Heterocyclyl polycyclic ring systems can include heteroatoms in one or more rings in the polycyclic ring system. Substituents may be present on one or more rings in the polycyclic ring system.
  • Spiro heterocyclyl refers to 5 to 12 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called as spiro atom) , wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO) , oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • spiro heterocyclyl include, but are not limited to the following groups:
  • Fused heterocyclyl refers to a 5 to 12 membered polycyclic heterocyclyl group, wherein each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, wherein one or more rings can contain one or more double bonds, but at least one of the rings does not have a completely conjugated ⁇ -electron system, and wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO) , oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C.
  • fused heterocyclyl include, but are not limited to the following groups:
  • Bridged heterocyclyl refers to a 5 to 12 membered polycyclic heterocyclyl group, wherein any two rings in the group share two disconnected atoms, the rings can have one or more double bonds but have no completely conjugated ⁇ -electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO) , oxygen, and sulfur, including sulfoxide and sulfone as ring atoms, the remaining ring atoms being C.
  • Representive examples of bridged heterocyclyl include, but are not limited to the following groups:
  • the carbocyclyl, the cycloalkyl, or the heterocyclyl may be unsubstituted, or be substituted with one or more substituents as valency allows, wherein the substituents can be independently selected from a number of groups such as oxo, -CN, halogen, alkyl and alkoxyl, opotionally, the alkyl substitution may be further substituted.
  • aryl refers to a 6 to 10 membered all-carbon monocyclic ring or a polycyclic fused ring (a “fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with other ring in the system) group, and has a completely conjugated ⁇ -electron system.
  • aryl may be used interchangeably with the terms “aryl ring” “carbocyclic aromatic ring” , “aryl group” and “carbocyclic aromatic group” .
  • Representive examples of aryl are phenyl and naphthyl.
  • heteroaryl refers to a monocyclic or multicyclic aromatic hydrocarbon in which at least one of the ring carbon atoms has been replaced with a heteroatom independently selected from oxygen, nitrogen and sulfur.
  • the heteroaryl is based on a C 5-10 aryl with one or more of its ring carbon atoms replaced by the heteroatom.
  • a heteroaryl group may be attached through a ring carbon atom or, where valency permits, through a ring nitrogen atom.
  • the heteroaryl may be unsubstituted, or be substituted with one or more substituents as valency allows with the substituents being independently selected from halogen, OH, alkyl, alkoxyl, and amino (e.g., NH 2 , NHalkyl, N (alkyl) 2 ) , optionally, the alkyl may be further substituted.
  • Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl) , imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl) , isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) , oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl) , oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl) , pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl) , pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl) , pyridyl (e.g., 2-pyrid
  • polycyclic aromatic heteroaryl groups examples include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.
  • a “substituted heteroaryl group” is substituted at any one or more substitutable ring atom, which is a ring carbon or ring nitrogen atom bonded to a hydrogen.
  • moieties e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl
  • substituents any substituents that are suitable to attach to the moiety.
  • Each R a1 and each R b1 are independently selected from –H and C 1-5 alkyl, optionally substituted with hydroxyl or C 1-3 alkoxy;
  • R c1 is –H, C 1-5 haloalkyl or C 1-5 alkyl, wherein the C 1-5 alkyl is optionally substituted with hydroxyl or C 1 -C 3 alkoxy.
  • pharmaceutically-acceptable salt refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1–19.
  • compositions of any one of the formulae described above include acid addition and base salts.
  • Suitable pharmaceutically acceptable salts of the compounds disclosed herein can form pharmaceutically acceptable salts with pharmaceutically acceptable acid (s) .
  • Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids) .
  • Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base (s) .
  • Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts) .
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of any one of the formulae described above may exhibit one or more kinds of isomerism (e.g. optical, geometric or tautomeric isomerism) .
  • isomerism e.g. optical, geometric or tautomeric isomerism
  • Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identifcal and are not mirror images of each other.
  • a compound When a compound is designated by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S” ) or its structure (e.g., the configuration is indicated by “wedge” bonds) that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99%or 99.9%optically pure (also referred to as “enantiomerically pure” ) .
  • Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair)
  • the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99%or 99.9%by weight.
  • the stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center.
  • a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”
  • the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.
  • Racemic mixture means 50%of one enantiomer and 50%of the corresponding enantiomer.
  • a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound.
  • geometric isomer means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a carbocyclic ring, or to a bridged bicyclic system.
  • Substituent atoms (other than hydrogen) on each side of a carbon- carbon double bond may be in an E or Z configuration according to the Cahn-Ingold-Prelog priority rules. In the “E” configuration, the substituents having the highest priorities are on opposite sides in relationship to the carbon-carbon double bond. In the “Z” configuration, the substituents having the highest priorities are oriented on the same side in relationship to the carbon-carbon double bond.
  • Substituents around a carbon-carbon double bond can also be referred to as “cis” or “trans, ” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • the arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans. ”
  • the term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans. ”
  • tautomeric isomerism ( “tautomerism” ) can occur. This can take the form of proton tautomerism in compounds of any one of the formulae described above containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • geometric isomer When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9%pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • racemate or a racemic precursor
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of any one of the formulae described above contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer (s) by means well known to a skilled person.
  • Chiral compounds of any one of the formulae described above (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50%by volume of isopropanol, typically from 2%to 20%, and from 0 to 5%by volume of an alkylamine, typically 0.1%diethylamine.
  • a compound of the present disclosure is administered in an amount effective to treat a condition as described herein.
  • the compounds of the present disclosure can be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt.
  • the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the present disclosure.
  • the compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally, or topically.
  • the compounds of the present disclosure may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.
  • the compounds of the present disclosure may also be administered directly into the bloodstream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • the compounds of the present disclosure may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • the compounds of the present disclosure can also be administered intranasally or by inhalation.
  • the compounds of the present disclosure may be administered rectally or vaginally.
  • the compounds of the present disclosure may also be administered directly to the eye or ear.
  • the dosage regimen for the compounds of the present disclosure and/or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely.
  • the total daily dose of a compound of the present disclosure is typically from about 0.001 to about 100 mg/kg (i.e., mg compound of the present disclosure per kg body weight) for the treatment of the indicated conditions discussed herein.
  • compositions may be provided in the form of tablets containing 0.1-500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient.
  • doses may range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
  • Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammal such as primates, rodents (mice, rats, hamsters, rabbits etc) .
  • humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
  • the present disclosure comprises pharmaceutical compositions.
  • Such pharmaceutical compositions comprise a compound of the present disclosure presented, a pharmaceutically acceptable salt, or a stereoisomer thereof with a pharmaceutically acceptable carrier or excipient.
  • Other pharmacologically active substances can also be present.
  • pharmaceutically acceptable carrier or excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition.
  • Pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.
  • compositions of present disclosure may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions) , dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the form depends on the intended mode of administration and therapeutic application.
  • compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general.
  • One mode of administration is parenteral (e.g. intravenous, subcutaneous, intraperitoneal, intramuscular) .
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure.
  • the oral administration may be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of any one of the formulae described above are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets may contain a controlled release formulation.
  • the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
  • oral administration may be in a liquid dose form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water) .
  • Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening) , and/or perfuming agents.
  • the present disclosure comprises a parenteral dose form.
  • Parenter administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion.
  • injectable preparations i.e., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting agents, and/or suspending agents may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • the present disclosure comprises a topical dose form.
  • Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration.
  • Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams.
  • a topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated -see, for example, Finnin and Morgan, J. Pharm. Sci., 88: 955-958, 1999.
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of present disclosure is dissolved or suspended in a suitable carrier.
  • a typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the compounds of the present disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
  • Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist) , or nebulizer, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the present disclosure comprises a rectal dose form.
  • rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • Compounds of the present disclosure can inhibit CDK2 and therefore are useful for treating diseases wherein the underlying pathology is, wholly or partially, mediated by CDK2.
  • diseases include cancer and other diseases with proliferation disorder.
  • the present disclosure provides treatment of an individual or a patient in vivo using a compound of Formula (I) , or a pharmaceutically acceptable salt, or a stereoisomer thereof such that growth of cancerous tumors is inhibited.
  • a compound of Formula (I) or of any of the formulae as described herein, or a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof can be used to inhibit the growth of cancerous tumors with aberrations that activate the CDK2 kinase activity.
  • CCNE1 diseases
  • diseases e.g., cancers
  • CCNE1 cyclin E1
  • the patient has been previously determined to have an amplification of the cyclin E1 (CCNE1) gene and/or an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than a control expression level of CCNE1.
  • a compound of Formula (I) or of any of the formulae as described herein, or a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof can be used in conjunction with other agents or standard cancer treatments, as described below.
  • the present disclosure provides a method for inhibiting growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a compound of Formula (I) or of any of the formulae as described herein, or of a compound as recited in any of the claims and described herein, or of a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the present disclosure provides a method for inhibiting growth of tumor cells with CCNE1 amplification and overexpression in an individual or a patient.
  • the method includes administering to the individual or patient in need thereof a therapeutically effective amount of a compound of Formula (I) or of any of the formulae as described herein, or of a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • compounds of the present disclosure selectively inhibit CDK2 over CDK1, with a ratio of IC 50 values for the latter (CDK1) against the former (CDK2) of at least about 2, 5, 10, 15, 20, 40, 50, 60, 80, 100 or more.
  • provided herein is a method of inhibiting CDK2, comprising contacting the CDK2 with a compound of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt, or a stereoisomer thereof.
  • a method of inhibiting CDK2 in a patient comprising administering to the patient a compound of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • a method for treating cancer includes administering to a patient (in need thereof) , a therapeutically effective amount of a compound of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the cancer is characterized by amplification or overexpression of CCNE1.
  • the cancer is characterized by inactivation of a CDK2 inhibitor, such as p21Cip1 or p27Kip1.
  • the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of CCNE1.
  • the patient has been diagnosed with a cancer characterized by amplification or overexpression of CCNE1, and/or loss of function of p21Cip1 or p27Kip1.
  • the method further comprises determining the status of expression of CCNE1, p21Cip1 and/or p27Kip1.
  • the method further comprises selecting patients characterized by amplification or overexpression of CCNE1, and/or loss of function of p21Cip1 or p27Kip1 for treatment.
  • provided herein is a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the disease or disorder associated with CDK2 is associated with an amplification of the cyclin E1 (CCNE1) gene and/or overexpression of CCNE1.
  • CCNE1 cyclin E1
  • the disease or disorder associated with CDK2 is N-myc amplified neuroblastoma cells (See Molenaar et al., Proc Natl Acad Sci USA, 106 (31) : 12968-12973) , K-Ras mutant lung cancers (see Hu, S., et al., Mol Cancer Ther, 2015, 14 (11) : 2576-85, and cancers with FBW7 mutation and CCNE1 overexpression (see Takada, et al., Cancer Res, 2017, 77 (18) : 4881-4893) .
  • the disease or disorder associated with CDK2 is breast, lung, colorectal, gastric, or bone cancer, leukemia or lymphoma.
  • the disease or disorder associated with CDK2 is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.
  • the disease or disorder associated with CDK2 is lung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or stomach adenocarcinoma.
  • the disease or disorder associated with CDK2 is an adenocarcinoma, carcinoma, or cystadenocarcinoma.
  • the disease or disorder associated with CDK2 is uterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.
  • the disease or disorder associated with CDK2 is a cancer.
  • the cancer is characterized by amplification or overexpression of CCNE1.
  • the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of CCNE1.
  • the breast cancer is chemotherapy or radiotherapy resistant breast cancer, endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/6 inhibition.
  • the breast cancer is advanced or metastatic breast cancer.
  • cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia
  • cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition-resistant melanoma) , renal cancer (e.g., clear cell carcinoma) , prostate cancer (e.g., hormone refractory prostate adenocarcinoma) , breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer) , squamous cell head and neck cancer, urothelial cancer (e.g., bladder) and cancers with high microsatellite instability (MSI high ) . Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.
  • melanoma e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition-resistant melanoma
  • renal cancer e.g., clear cell carcinoma
  • prostate cancer e.g., hormone re
  • cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.
  • solid tumors e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.
  • lymphoma e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL) , acute myelogenous leukemia (AML) , chronic lymphocytic leukemia (CLL) , chronic myelogenous leukemia (CML) , DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular) , Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • DLBCL mantle cell lymphoma
  • Non-Hodgkin lymphoma including relapsed or refractory NHL and recurrent follicular
  • cancers that are treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing’s sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, ure
  • diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.
  • Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL) , acute myelogenous leukemia (AML) , acute promyelocytic leukemia (APL) , chronic lymphocytic leukemia (CLL) , chronic myelogenous leukemia (CML) , diffuse large B-cell lymphoma (DLBCL) , mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular) , Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF) , polycythemia vera (PV) , and essential thrombocytosis (ET) ) , myelodysplasia syndrome (MDS) , T-cell acute lymphoblastic lymphoma (T-ALL) and multiple myelo
  • Exemplary sarcomas include chondrosarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.
  • Exemplary lung cancers include non-small cell lung cancer (NSCLC) , small cell lung cancer (SCLC) , bronchogenic carcinoma, squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • bronchogenic carcinoma squamous cell
  • undifferentiated small cell undifferentiated large cell
  • adenocarcinoma undifferentiated small cell
  • adenocarcinoma alveolar (bronchiolar) carcinoma
  • bronchial adenoma chondromatous hamartoma
  • mesothelioma mesothelioma.
  • Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) , and colorectal cancer.
  • esophagus squamous cell carcinoma, a
  • Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma] ) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) .
  • liver cancers include hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.
  • Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors.
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma malignant fibrous histiocytoma
  • chondrosarcoma chondrosarcoma
  • Ewing's sarcoma malignant lymphoma
  • multiple myeloma malignant giant cell tumor chordoma
  • Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , and spinal cord (neurofibroma, meningioma, glioma, sarcoma) , as well as neuroblastoma and Lhermitte-Duclos disease.
  • skull osteoma, hemangioma, granuloma,
  • Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma) , cervix (cervical carcinoma, pre -tumor cervical dysplasia) , ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , and fallopian tubes (carcinoma) .
  • endometrial carcinoma endometrial carcinoma
  • cervix cervical carcinoma,
  • Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.
  • diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia) , triple-negative breast cancer (TNBC) , myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.
  • compounds of Formula (I) may possess satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolism and pharmacokinetic properties, solubility, and permeability. It will be understood that determination of appropriate biopharmaceutical properties is within the knowledge of a person skilled in the art, e.g., determination of cytotoxicity in cells or inhibition of certain targets or channels to determine potential toxicity.
  • mice preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • treatment refers to reversing, alleviating, or inhibiting the progress of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed (i.e., therapeutic treatment) .
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (i.e., prophylactic treatment) (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen) .
  • Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • condition ” “disease, ” and “disorder” are used interchangeably.
  • administer refers to methods introducing a compound disclosed herein, or a composition thereof, in or on a patient. These methods include, but are not limited to, intraarticular (in the joints) , intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition) , Mack Publishing Co., Easton, Pa.
  • an effective amount of a compound taught herein varies depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • An effective amount of a compound of the present teachings may be readily determined by one of ordinary skill by routine methods known in the art.
  • terapéuticaally effective amount means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control.
  • a therapeutically effective amount can be an amount effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the 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 disease, the particular anticancer agent, its mode of administration, combination treatment with other therapies, and the like.
  • Cancer cell growth and survival can be impacted by dysfunction in multiple signaling pathways.
  • Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, and/or reduce the toxicity of treatment.
  • One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-estrogen agents, anti-inflammatory agents, steroids, immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and CDK4/6 kinase inhibitors such as, for example, those described in WO 2006/056399 can be used in combination with the compounds of the present disclosure for treatment of CDK2-associated diseases, disorders or conditions.
  • Other agents such as therapeutic antibodies can be used in combination with the compounds of the present disclosure for treatment of CDK2-associated diseases, disorders or conditions.
  • the one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
  • the CDK2 inhibitor is administered or used in combination with an anti-estrogen agent or a CDK4/6 inhibitor or a mTOR inhibitor or a BCL2 inhibitor or a chemotherapy.
  • the compounds as disclosed herein can be used in combination with one or more other enzyme/protein/receptor inhibitors therapies for the treatment of diseases, such as cancer and other diseases or disorders described herein.
  • diseases and indications treatable with combination therapies include those as described herein.
  • cancers include solid tumors and non-solid tumors, such as liquid tumors, blood cancers.
  • infections include viral infections, bacterial infections, fungus infections or parasite infections.
  • the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4/6, TGF-DR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGF ⁇ R, PDGF ⁇ R, PI3K (alpha, beta, gamma, delta, and multiple or selective) , CSF1R, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3) , FLT3, VEGFR/
  • the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infections.
  • inhibitors that can be combined with the compounds of the present disclosure for treatment of cancer and infections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCB54828) , INCB62079) , an EGFR inhibitor (also known as ErB-1 or HER-1; e.g., erlotinib, gefitinib, vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab) , a VEGFR inhibitor or pathway blocker (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib,
  • FGFR inhibitor
  • the compound or salt described herein is administered with a PI3K6 inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib) . In some embodiments, the compound or salt described herein is administered with a JAK1 inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK1 inhibitor, which is selective over JAK2.
  • Example antibodies for use in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2) , ranibizumab (e.g., anti-VEGF-A) , bevacizumab (AVASTINTM , e.g., anti-VEGF) , panitumumab (e.g., anti-EGFR) , cetuximab (e.g., anti-EGFR) , rituxan (e.g., anti-CD20) , and antibodies directed to c-MET.
  • trastuzumab e.g., anti-HER2
  • ranibizumab e.g., anti-VEGF-A
  • bevacizumab AVASTINTM , e.g., anti-VEGF
  • panitumumab e.g., anti-EGFR
  • cetuximab e.g., anti-EGFR
  • rituxan e.g., anti
  • cytostatic agent cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778, 123, BMS 214662, IRESSATM (gefitinib) , TARCEVATM (erlotinib) , antibodies to EGFR, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine
  • the compounds of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery.
  • immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2) , CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, bispecific or multi-specific antibody, antibody drug conjugate, adoptive T cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapy and immunomodulating small molecules, including thalidomide or JAK1/2 inhibitor, PI3Kd inhibitor and the like.
  • the compounds can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutic agent.
  • chemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine,
  • chemotherapeutics include proteasome inhibitors (e.g., bortezomib) , thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.
  • proteasome inhibitors e.g., bortezomib
  • thalidomide thalidomide
  • revlimid thalidomide
  • DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.
  • Example steroids include corticosteroids such as dexamethasone or prednisone.
  • Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC TM ) , nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts.
  • Other example suitable Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491.
  • Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and their pharmaceutically acceptable salts.
  • Other example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.
  • Example suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and their pharmaceutically acceptable salts.
  • Other example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444.
  • Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptable salts.
  • Other example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402.
  • Example suitable CDK4/6 inhibitors include palbociclib, ribociclib, trilaciclib, lerociclib, and abemaciclib, and their pharmaceutically acceptable salts.
  • Other example suitable CDK4/6 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074, and WO 12/061156.
  • the compounds of the disclosure can be used in combination with one or more other kinase inhibitors including imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors.
  • the compounds of the disclosure can be used in combination with a chemotherapeutic in the treatment of cancer, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects.
  • the compounds of the disclosure can be used in combination with a chemotherapeutic provided herein.
  • additional pharmaceutical agents used in the treatment of multiple myeloma can include, without limitation, melphalan, melphalan plus prednisone [MP] , doxorubicin, dexamethasone, and Velcade (bortezomib) .
  • the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent.
  • an alkylating agent include cyclophosphamide (CY) , melphalan (MEL) , and bendamustine.
  • the proteasome inhibitor is carfilzomib.
  • the corticosteroid is dexamethasone (DEX) .
  • the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM) . Additive or synergistic effects are desirable outcomes of combining a CDK2 inhibitor of the present disclosure with an additional agent.
  • the agents can be combined with the present compound in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • the compounds of the present disclosure can be used in combination with one or more other inhibitors or one or more therapies for the treatment of infections.
  • infections include viral infections, bacterial infections, fungus infections or parasite infections.
  • a corticosteroid such as dexamethasone is administered to a patient in combination with the compounds of the disclosure where the dexamethasone is administered intermittently as opposed to continuously.
  • the compounds of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules) , cells, and cells transfected with genes encoding immune stimulating cytokines.
  • tumor vaccines include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.
  • tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV) , Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV) .
  • HPV Human Papilloma Viruses
  • HBV and HCV Hepatitis Viruses
  • KHSV Kaposi's Herpes Sarcoma Virus
  • the compounds of the present disclosure can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor tissue itself.
  • the compounds of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with dendritic cells immunization to activate potent anti-tumor responses.
  • the compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells.
  • the compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.
  • combinations of the compounds of the disclosure with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplant or stem cell transplant.
  • the compounds of the present disclosure can be used in combination with bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin.
  • the compounds of Formula (I) or any of the formulae as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens.
  • pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, &C) , Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.
  • Viruses causing infections treatable by methods of the present disclosure include, but are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus) , flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • human papillomavirus influenza, hepatitis A
  • Pathogenic bacteria causing infections treatable by methods of the disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • Pathogenic fungi causing infections treatable by methods of the disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc. ) , Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc. ) , Genus Mucorales (mucor, absidia, rhizophus) , Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • Candida albicans, krusei, glabrata, tropicalis, etc.
  • Cryptococcus neoformans Aspergillus (fumigatus, niger, etc. )
  • Genus Mucorales micor, absidia, rhizophus
  • Sporothrix schenkii Blastomyces dermatitidis
  • Pathogenic parasites causing infections treatable by methods of the disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.
  • more than one pharmaceutical agent When more than one pharmaceutical agent is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents) .
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB) , ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TIGIT, CD112R, VISTA, PD-1, PD-L1 and PD-L2.
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB) , ICOS, A2AR, B7
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137.
  • the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA.
  • the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
  • the compounds provided herein can be used in combination with one or more agonists of immune checkpoint molecules, e.g., OX40, CD27, GITR, and CD137 (also known as 4-1B) .
  • immune checkpoint molecules e.g., OX40, CD27, GITR, and CD137 (also known as 4-1B) .
  • the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
  • the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475) , pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224.
  • the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab.
  • the anti-PD1 antibody is pembrolizumab.
  • the anti-PD-1 monoclonal antibody is MGA012.
  • the anti-PD1 antibody is SHR-1210.
  • Other anti-cancer agent (s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab) .
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody.
  • the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446) , or MSB0010718C.
  • the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 bispecific antibody.
  • the anti-PD-1/PD-L1 is MCLA-136.
  • the inhibitor is MCLA-145.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675, 206.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody.
  • the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.
  • the inhibitor of an immune checkpoint molecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.
  • OX40 e.g., OX40 agonist antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178.
  • the OX40L fusion protein is MEDI6383.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody.
  • the anti-CD20 antibody is obinutuzumab or rituximab.
  • the compounds of the present disclosure can be used in combination with bispecific antibodies.
  • one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGFb receptor.
  • the compounds of the disclosure can be used in combination with one or more metabolic enzyme inhibitors.
  • the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase.
  • IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.
  • the additional compounds, inhibitors, agents, etc. can be combined with the present compound in a single or continuous dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.
  • kits for conveniently and effectively carrying out the methods or uses in accordance with the present invention.
  • the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • kits are especially suited for the delivery of solid oral forms such as tablets or capsules.
  • a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use.
  • a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
  • Optionally associated with such container (s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the compounds of any one of the formulae described above may be prepared by the general and specific methods described below, using the common general knowledge of one skilled in the art of synthetic organic chemistry. Such common general knowledge can be found in standard reference books such as Comprehensive Organic Chemistry, Ed. Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I-XII (published by Wiley-Interscience) .
  • the starting materials used herein are commercially available or may be prepared by routine methods known in the art.
  • certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step.
  • Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl (Boc) , benzyloxycarbonyl (Cbz) , and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the any one of the formulae described above compounds.
  • Step 1 benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) carbamate
  • Step 2 benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4- fluoro-1H-pyrazol-5-yl) carbamate
  • Step 3 1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4-fluoro-1H- pyrazol-5-amine
  • Step 2 4-bromo-2-methylpyrazolo [1, 5-a] pyrazine
  • Step 3 N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldimethylsilyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) -2-methylpyrazolo [1, 5-a] pyrazin-4-amine
  • Step 4 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentan-1-ol (Intermediate 2)
  • Step 5 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 6 (1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate
  • Step 1 N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldiphenylsilyl) oxy) cyclopentyl) -4-fluoro- 1H-pyrazol-5-yl) -2-methylpyrazolo [1, 5-a] pyrazin-4-amine
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4- yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol
  • the reaction mixture was cooled, diluted with EtOAc (50 mL) and washed with saturated aqueous of NH 4 Cl (40 mL) and brine (10 mL) .
  • the organic phase was dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • Step 3 (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4- yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate
  • Step 4 (1R, 3S) -3- (1- (tert-butyl) -4-fluoro-5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4- yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 5 (1R, 3S) -3- (4-fluoro-3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-5-yl) cyclopentyl isopropylcarbamate
  • Step 1 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentyl (1-methylcyclobutyl) carbamate
  • Step 3 (1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5- yl) cyclopentyl (1-methylcyclobutyl) carbamate
  • Step 1 (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentan-1-ol
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 3 (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbama te
  • Step 1 (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazin-2-ylamino) -1H-pyrazol-3-yl) cyclopentyl (1-hydroxy- 2-methylpropan-2-yl) carbamate
  • Step 2 2-methyl-2- ( ( ( ( (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) oxy) carbonyl) amino) propyl 2, 2, 2-trifluoroacetate
  • Step 3 (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl (1-hydroxy-2- methylpropan-2-yl) carbamate
  • Step 1 4-nitrophenyl ( (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl) carbonate
  • Step 2 (1R, 3S) -3- (3- (pyrazin-2-ylamino) -1H-pyrazol-5-yl) cyclopentyl (2-cyanopropan-2- yl) carbamate
  • Step 2 2- ( ( (tert-butyldimethylsilyl) oxy) methyl) -6-chloropyrazine
  • Step 3 (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentan-1-ol
  • Step 4 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate
  • Step 5 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 6 (6- ( (5- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-3- yl) amino) pyrazin-2-yl) methyl 2, 2, 2-trifluoroacetate
  • Step 7 (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate
  • Step 1 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyrazin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl ( (S) -sec-butyl) carbamate
  • Step 2 (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl ( (S) -sec-butyl) carbamate
  • Step 1 (6- ( (5- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) -1H-pyrazol-3- yl) amino) pyrazin-2-yl) methyl 2, 2, 2-trifluoroacetate
  • Step 2 (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyrazin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl (1-methylcyclopropyl) carbamate
  • Step 1 (cis, rac) -N- (3- (3- ( (3-bromopyridin-2-yl) oxy) cyclopentyl) -1- (tert-butyl) -1H- pyrazol-5-yl) pyrazin-2-amine
  • Step 2 (cis, rac) -N- (1- (tert-butyl) -3- ( 3- ( (3- (prop-1-en-2-yl) pyridin-2-yl) oxy) cyclopentyl) - 1H-pyrazol-5-yl) pyrazin-2-amine
  • Step 3 (cis, rac) -N- (1- (tert-butyl) -3- (3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H- pyrazol-5-yl) pyrazin-2-amine
  • Step 4 N- (5- ( (1S, 3R) -3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H-pyrazol-3- yl) pyrazin-2-amine and N- (5- ( (1R, 3S) -3- ( (3-isopropylpyridin-2-yl) oxy) cyclopentyl) -1H- pyrazol-3-yl) pyrazin-2-amine
  • Step 1 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-chloropyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 3 (1R, 3S) -3- (5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 4 (1R, 3S) -3- (5- ( (2-hydroxypyrimidin-4-yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 1 (1R, 3S) -3- (1- (tert-butyl) -5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentan- 1-ol
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- (pyrimidin-4-ylamino) -1H-pyrazol-3-yl) cyclopentyl (4-nitrophenyl) carbonate
  • Step 3 4-nitrophenyl ( (1R, 3S) -3- (3- (pyrimidin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl) carbonate
  • Step 4 (1R, 3S) -3- (3- (pyrimidin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl (3- methyloxetan-3-yl) carbamate
  • Step 1 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentan-1-ol
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl (4-nitrophenyl) carbonate
  • Step 3 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl bicyclo [1.1.1] pentan-1-ylcarbamate
  • Step 4 (1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl bicyclo [1.1.1] pentan-1-ylcarbamate
  • Step 1 N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert-butyldimethylsilyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) -2-methylpyrimidin-4-amine
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentan-1-ol
  • Step 3 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-3- yl) cyclopentyl (4-nitrophenyl) carbonate
  • Step 4 (1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (4- nitrophenyl) carbonate
  • Step 5 (1R, 3S) -3- (3- ( (2-methylpyrimidin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (3- methyloxetan-3-yl) carbamate
  • Step 1 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5- yl) amino) nicotinonitrile
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-3- yl) cyclopentyl (4-nitrophenyl) carbonate
  • Step 3 (1R, 3S) -3- (5- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-3-yl) cyclopentyl (4- nitrophenyl) carbonate
  • Step 4 (1R, 3S) -3- (3- ( (5-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (1- hydroxy-2-methylpropan-2-yl) carbamate
  • Step 1 2- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5- yl) amino) isonicotinonitrile
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-3- yl) cyclopentyl (4-nitrophenyl) carbonate
  • Step 3 (1R, 3S) -3- (3- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl (4- nitrophenyl) carbonate
  • Step 4 (1R, 3S) -3- (3- ( (4-cyanopyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl ( (1r, 3R) - 3-hydroxycyclobutyl) carbamate
  • Step 1 benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( ( (4-nitrophenoxy) carbonyl) oxy) cyclopentyl) - 1H-pyrazol-5-yl) carbamate
  • Step 2 benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) carbamate
  • Step 3 (1R, 3S) -3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate (Intermediate 3)
  • Step 4 (1R, 3S) -3- (1- (tert-butyl) -5- (pyrazolo [1, 5-a] pyrimidin-5-ylamino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate
  • Step 5 (1R, 3S) -3- (3- (pyrazolo [1, 5-a] pyrimidin-5-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate
  • Step 1 (1R, 3S) -3- (1- (tert-butyl) -5- ( (4-chloropyridin-2-yl) amino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate
  • Step 2 (1R, 3S) -3- (5- ( [3, 4'-bipyridin] -2'-ylamino) -1- (tert-butyl) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate
  • the mixture was warmed to 110 °C and stirred at that temperature for 5 h.
  • the mixture was cooled and concentrated under reduced pressure, diluted with water (10 mL) and extracted with DCM (10 mL ⁇ 3) .
  • the combined organic phases were washed with brine (10 mL) , dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 3 (1R, 3S) -3- (3- ( [3, 4'-bipyridin] -2'-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- ( (4- (1-methyl-1H-pyrazol-3-yl) pyridin-2-yl) amino) - 1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 3 (1R, 3S) -3- (3- ( (4- (1-methyl-1H-pyrazol-3-yl) pyridin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate
  • Step 1 (1R, 3S) -3- (1- (tert-butyl) -5- ( (1- (methylsulfonyl) piperidin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 2 (1R, 3S) -3- (3- ( (1- (methylsulfonyl) piperidin-4-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate
  • Step 1 2-bromo-6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridine
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentan-1-ol
  • Step 3 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate
  • Step 4 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 5 (1R, 3S) -3- (3- ( (6- (hydroxymethyl) pyridin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate
  • Step 2 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol- 3-yl) cyclopentan-1-ol
  • Step 3 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol- 3-yl) cyclopentyl 1H-imidazole-1-carboxylate
  • Step 4 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol- 3-yl) cyclopentyl isopropylcarbamate
  • Step 5 (1R, 3S) -3- (3- ( (6- (methoxymethyl) pyridin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate
  • Example 47 (1R, 3S) -3- (3- (pyrazolo [1, 5-a] pyrazin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate and Example 48 (1R, 3S) -3- (3- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate
  • Step 3 2, 4-dibromopyrazolo [1, 5-a] pyrazine
  • Step 4 2-bromo-N- (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (tert- butyldimethylsilyl) oxy) cyclopentyl) -1H-pyrazol-5-yl) pyrazolo [1, 5-a] pyrazin-4-amine
  • Step 5 (1R, 3S) -3- (5- ( (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino) -1- (tert-butyl) -1H- pyrazol-3-yl) cyclopentan-1-ol
  • Step 6 (1R, 3S) -3- (5- ( (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino) -1- (tert-butyl) -1H- pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate
  • Step 7 (1R, 3S) -3- (5- ( (2-bromopyrazolo [1, 5-a] pyrazin-4-yl) amino) -1- (tert-butyl) -1H- pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 8 (1R, 3S) -3- (1- (tert-butyl) -5- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4- yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 9 (1R, 3S) -3- (3- ( (2- (methoxymethyl) pyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-5-yl) cyclopentyl isopropylcarbamate
  • Step 10 (1R, 3S) -3- (3- (pyrazolo [1, 5-a] pyrazin-4-ylamino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate
  • Step 2 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5-yl) amino) -N- methylpicolinamide
  • Step 3 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H- pyrazol-3-yl) cyclopentyl 1H-imidazole-1-carboxylate
  • Step 4 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H- pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 5 (1R, 3S) -3- (3- ( (6- (methylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-5- yl) cyclopentyl isopropylcarbamate
  • Example 50 (1R, 3S) -3- (3- ( (6-carbamoylpyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate ,
  • Example 51 (1R, 3S) -3- (5- ( (6- (isopropylcarbamoyl) pyridin-2- yl) amino) -1H-pyrazol-3-yl) cyclopentyl isopropylcarbamate, and
  • Example 52 6- ( (5- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-3-yl) amino) picolinic acid
  • Step 2 methyl 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3-hydroxycyclopentyl) -1H-pyrazol-5- yl) amino) picolinate
  • Step 3 methyl 6- ( (3- ( (1S, 3R) -3- ( (1H-imidazole-1-carbonyl) oxy) cyclopentyl) -1- (tert- butyl) -1H-pyrazol-5-yl) amino) picolinate
  • Step 4 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6- (isopropylcarbamoyl) pyridin-2-yl) amino) -1H- pyrazol-3-yl) cyclopentyl isopropylcarbamate
  • Step 5 6- ( (1- (tert-butyl) -3- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H- pyrazol-5-yl) amino) picolinic acid
  • Step 6 (1R, 3S) -3- (1- (tert-butyl) -5- ( (6-carbamoylpyridin-2-yl) amino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate
  • Step 7 (1R, 3S) -3- (3- ( (6-carbamoylpyridin-2-yl) amino) -1H-pyrazol-5-yl) cyclopentyl isopropylcarbamate
  • Step 8 6- ( (5- ( (1S, 3R) -3- ( (isopropylcarbamoyl) oxy) cyclopentyl) -1H-pyrazol-3- yl) amino) picolinic acid
  • Step 9 (1R, 3S) -3- (5- ( (6- (isopropylcarbamoyl) pyridin-2-yl) amino) -1H-pyrazol-3- yl) cyclopentyl isopropylcarbamate
  • Step 1 ethyl (E) -2- (3- (5- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3- yl) cyclopentylidene) acetate
  • Step 2 ethyl 2- (3- (5-amino-1- (tert-butyl) -1H-pyrazol-3-yl) cyclopentyl) acetate
  • Step 3 ethyl 2- (3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H- pyrazol-3-yl) cyclopentyl) acetate
  • Step 4 2- (3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol- 3-yl) cyclopentyl) acetic acid
  • Step 5 2- (3- (1- (tert-butyl) -5- ( (2-methylpyrazolo [1, 5-a] pyrazin-4-yl) amino) -1H-pyrazol- 3-yl) cyclopentyl) -N-isopropylacetamide
  • reaction mixture was stirred at that temperature for 2 h before it was quenched with water (5.0 mL) and then extracted with CH 2 Cl 2 (15 mL ⁇ 2) . The combined organic phases were dried over Na 2 SO 4 and then filtered. The filtrate was concentrated under reduced pressure.
  • Step 6 (cis, rac) -N-isopropyl-2- ( (1R, 3S) -3- (3- ( (2-methylpyrazolo [1, 5-a] pyrazin-4- yl) amino) -1H-pyrazol-5-yl) cyclopentyl) acetamide
  • Step 1 ethyl 3- (bromomethyl) -1-methyl-1H-pyrazole-5-carboxylate
  • Step 2 3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxylic acid
  • Step 3 benzyl (1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol- 5-yl) carbamate
  • Step 4 1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-5-amine
  • Step 5 N- (1- (tert-butyl) -3- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) -1H-pyrazol-5-yl) - 3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide
  • Step 6 3- (methoxymethyl) -1-methyl-N- (5- ( (1S, 3R) -3- (pyrimidin-2-yloxy) cyclopentyl) - 1H-pyrazol-3-yl) -1H-pyrazole-5-carboxamide
  • Step 1 (trans, rac) -3- (5- ( ( (benzyloxy) carbonyl) amino) -1- (tert-butyl) -1H-pyrazol-3- yl) cyclopentyl methanesulfonate
  • Step 2 (cis, rac) -benzyl (1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) - 1H-pyrazol-5-yl) carbamate
  • Step 3 (cis, rac) -1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) -1H- pyrazol-5-amine
  • Step 4 (cis, rac) -N- (1- (tert-butyl) -3- (3- ( (1-methyl-1H-pyrazol-3-yl) oxy) cyclopentyl) -1H- pyrazol-5-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide
  • Step 5 (cis, rac) -3- (methoxymethyl) -1-methyl-N- (5- (3- ( (1-methyl-1H-pyrazol-3- yl) oxy) cyclopentyl) -1H-pyrazol-3-yl) -1H-pyrazole-5-carboxamide
  • Step 3 5-bromo-2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridine (Intermediate 4)
  • Step 4 3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopent-2-en-1-one
  • the mixture was warmed to 100 °C and stirred at that temperature for 2 h.
  • the reaction was diluted with water (20 mL) and extracted with DCM (20 mL ⁇ 3) .
  • the combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 .
  • the mixture was filtered and concentrated under reduced pressure.
  • Step 5 (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentan-1-ol (Intermediate 5)
  • Step 6 (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl 1H-imidazole-1-carboxylate
  • Step 7 (cis, rac) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate
  • the reaction was diluted with water (10 mL) and extracted with DCM (10 mL ⁇ 3) . The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 . The mixture was filtered and concentrated under reduced pressure.
  • Step 8 (1R, 3S) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate and (1S, 3R) -3- (2- (1-methyl-1H-pyrazol-5-yl) -1H- pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate
  • Step 1 (cis, rac) - 3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl (4-nitrophenyl) carbonate
  • Step 2 (cis, rac) - 3- (2- (1-methyl-1H-pyrazol-5-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl cyclopropylcarbamate
  • Step 3 (cis, rac) - 3- (2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl cyclopropylcarbamate
  • Step 1 (cis, rac) - 3- (3-bromo-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate
  • Step 2 (cis, rac) - 3- (3-methyl-2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentyl isopropylcarbamate
  • Step 2 3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent-2-en-1-one
  • Step 3 (cis, rac) - 3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentan-1-ol
  • Step 4 (cis, rac) - 3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl 1H- imidazole-1-carboxylate
  • Step 5 (cis, rac) - 3- (2-methyl-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarba-mate
  • Step 6 (cis, rac) - 3- (2-methyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate
  • Step 1 5-bromo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine
  • Step 2 3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopent- 2-en-1-one
  • Step 3 (rac) -3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopent-2-en-1-ol
  • Step 4 (cis, rac) - 3- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridin-5- yl) cyclopentan-1-ol (Intermediate 6)
  • Step 5 (cis, rac) - 3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentan-1-ol
  • Step 6 (cis, rac) - 3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl 1H-imidazole-1-carboxylate
  • Step 7 (cis, rac) - 3- (2-iodo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl isopropylcarbamate (Intermediate 7)
  • Step 8 (cis, rac) - 3- (2-phenyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3- b] pyridin-5-yl) cyclopentyl isopropylcarbamate
  • Step 9 (cis, rac) - 3- (2-phenyl-1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate
  • Step 1 (cis, rac) - 3- (2- (1-methyl-1H-indazol-5-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) - 1H-pyrrolo [2, 3-b] pyridin-5-yl) cyclopentyl isopropylcarbamate

Abstract

La présente invention concerne un composé représenté par la formule structurale (I) : ou un sel pharmaceutiquement acceptable, ou un stéréoisomère de celui-ci et leur utilisation dans, par exemple, le traitement d'une maladie ou d'un trouble associé à CDK2. La présente invention concerne également des compositions les contenant ainsi que des procédés d'utilisation et de fabrication de celles-ci.
PCT/CN2022/080313 2021-12-24 2022-03-11 Cyclopentanes substitués utilisés en tant qu'inhibiteurs de cdk2 WO2023168686A1 (fr)

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WO2024051727A1 (fr) * 2022-09-09 2024-03-14 楚浦创制（武汉）医药科技有限公司 Dérivé de pyrazole, composition pharmaceutique et utilisation
WO2024056019A1 (fr) * 2022-09-15 2024-03-21 Beigene, Ltd. Composés bicycliques utilisés en tant qu'inhibiteurs de cdk

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