WO2016040515A1 - Substituted piperidine compounds - Google Patents

Substituted piperidine compounds Download PDF

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Publication number
WO2016040515A1
WO2016040515A1 PCT/US2015/049235 US2015049235W WO2016040515A1 WO 2016040515 A1 WO2016040515 A1 WO 2016040515A1 US 2015049235 W US2015049235 W US 2015049235W WO 2016040515 A1 WO2016040515 A1 WO 2016040515A1
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WIPO (PCT)
Prior art keywords
cancer
alkyl
cell
tumor
carcinoma
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PCT/US2015/049235
Other languages
French (fr)
Inventor
Lorna Helen Mitchell
Andrew Simon Bell
Richard Chesworth
Megan Alene Cloonan FOLEY
Kevin Wayne Kuntz
James Edward John Mills
Michael John Munchhof
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Epizyme, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MX2017002986A priority Critical patent/MX2017002986A/en
Application filed by Epizyme, Inc. filed Critical Epizyme, Inc.
Priority to CA2960280A priority patent/CA2960280A1/en
Priority to SG11201701597RA priority patent/SG11201701597RA/en
Priority to AU2015315182A priority patent/AU2015315182A1/en
Priority to KR1020177009316A priority patent/KR20170047397A/en
Priority to BR112017004589A priority patent/BR112017004589A2/en
Priority to CN201580060918.8A priority patent/CN107072207A/en
Priority to EA201790327A priority patent/EA201790327A1/en
Priority to US15/510,588 priority patent/US10577363B2/en
Priority to EP15840497.0A priority patent/EP3193605A4/en
Priority to JP2017513207A priority patent/JP2017528464A/en
Publication of WO2016040515A1 publication Critical patent/WO2016040515A1/en
Priority to IL250888A priority patent/IL250888A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure provides substituted piperidines as SMYD protein inhibitors, such as SMYD3 and SMYD2 inhibitors, and therapeutic methods of treating conditions and diseases wherein inhibition of SMYD proteins such as SMYD3 and SMYD2 provides a benefit.
  • Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases.
  • Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence.
  • epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin.
  • methyltransferases e.g., SMYD proteins such as SMYD3 and SMYD2
  • the present disclosure provides substituted piperidine compounds represented by any one of Formulae I-X below, and the pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as "Compounds of the Disclosure.”
  • the present disclosure provides a Compound of the Disclosure and one or more pharmaceutically acceptable carriers.
  • the present disclosure provides a method of inhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a mammal, comprising administering to the mammal an effective amount of at least one Compound of the Disclosure.
  • SMYD proteins such as SMYD3 or SMYD2
  • the present disclosure provides methods for treating a disease, disorder, or condition, e.g., cancer, responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, comprising administering a therapeutically effective amount of a Compound of the Disclosure.
  • a disease, disorder, or condition e.g., cancer
  • SMYD proteins such as SMYD3 or SMYD2
  • the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD3.
  • the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD2.
  • the present disclosure provides the use of Compounds of the Dicslosure as inhibitors of SMYD proteins.
  • the present disclosure provides a pharmaceutical composition for treating a disease, disorder, or condition responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Compound of the Disclosure in a mixture with one or more pharmaceutically acceptable carriers.
  • the present disclosure provides Compounds of the Disclosure for use in treating cancer in a mammal, e.g., breast, cervical, colon, kidney, liver, head and neck, skin, pancreatic, ovary, esophageal, lung, and prostate cancer.
  • a mammal e.g., breast, cervical, colon, kidney, liver, head and neck, skin, pancreatic, ovary, esophageal, lung, and prostate cancer.
  • the present disclosure provides a Compound of the Disclosure for use in the manufacture of a medicament for treating cancer in a mammal.
  • the present disclosure provides kit comprising a Compound of the Disclosure.
  • One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD3.
  • the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD3.
  • One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD2.
  • the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD2.
  • Compounds of the Disclosure are compounds having Formula I:
  • Z is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, [(cycloalkyl)alkylamino]alky
  • R 1 is selected from the group consisting of ethyl, n-propyl, isopropyl, isobutyl, and cyclopropyl;
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; or
  • R 2a and R 2b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 3a and R 3b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 4a and R 4b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 5a and R 5b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 2a and R 5a taken together form a C 1-4 bridge; and R 2b , R 3a , R 3b , R 4a , R 4b , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 3a and R 4a taken together form a C 1-4 bridge; and R 2a , R 2b , R 3b , R 4a , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 2a and R 4a taken together form a C 1-4 bridge; and R 2b , R 3a , R 3b , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or [0033] R 3a and R 5a taken form a C 1-4 bridge; and R 2a , R 2b , R 3b , R 4a , R 4b , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;
  • R 6 is selected from the group consisting of hydrogen and C 1-4 alkyl
  • R 7 is selected from the group consisting of hydrogen and C 1-4 alkyl
  • R 9 is selected from the group consisting of hydrogen and C 1-4 alkyl
  • R 10 is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, and (dialkylamino)alkyl;
  • R 11 is selected from the group consisting of hydrogen and C 1-4 alkyl.
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is selected from the group consisting of ethyl and cyclopropyl.
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of optionally substituted C 1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C 3-12 cycloalkyl, aralkyl, and heteroaralkyl, when X is
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is: ;
  • R 6 is selected from the group consisting of hydrogen and C 1-4 alkyl; and R 1 , X, and Z are as defined above in connection with Formula I. In another embodiment, R 6 is selected from the group consisting of hydrogen and methyl. In another embodiment, R 6 is hydrogen. [0043] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
  • R 2a is selected from the group consisting of halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; and R 1 , X, and Z are as defined above in connection with Formula I.
  • B is selected from the rou consistin of:
  • R 2a is selected from the group consisting of methyl, ethyl, phenyl, -CF 3 , -CO 2 Et, and -CH 2 OH. In another embodiment, R 2a is -CH 2 Ph.
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
  • R 3a is selected from the group consisting of halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; and R 1 , X, and Z are as defined above in connection with Formula I.
  • B is selected from the rou consistin of:
  • R 3a is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, and -CH 2 Ph. In another embodiment, R 3a is -CH 2 Ph.
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
  • R 2a and R 2b are each independently selected from the group consisting of halo and C 1-6 alkyl; or R 2a and R 2b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 1 , X, and Z are as defined above in connection with Formula I.
  • B is selected from the group consisting of:
  • B is selected from the group consisting of:
  • B is selected from the group consisting of:
  • R 2a and R 2b are each independently selected from the group consisting of halo and C 1-4 alkyl. In another embodiment, R 2a and R 2b are selected from the group consisting of fluoro and methyl. [0046] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
  • R 3a and R 3b are each independently selected from the group consisting of halo and C 1-6 alkyl; or
  • R 3a and R 3b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 1 , X, and Z are as defined above in connection with Formula I.
  • B is selected from the group consisting of:
  • B is selected from the group consisting of:
  • B is selected from the group consisting of:
  • R 3a and R 3b are each independently selected from the group consisting of halo and C 1-4 alkyl. In another embodiment, R 3a and R 3b are selected from the group consisting of fluoro and methyl. [0047] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
  • R 3a and R 5a are each independently C 1-6 alkyl; or R 3a and R 5a taken together form a C 1-4 bridge; and R 1 , X, and Z are as defined above in connection with Formula I.
  • B is selected from the group consisting of:
  • R 3a and R 5a are each independently C 1-4 alkyl. In another embodiment, R 3a and R 5a are each methyl or ethyl.
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
  • R 1 , X, and Z are as defined above in connection with Formula I.
  • B is selected from the group consisting of: .
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
  • R 2a and R 3a are each independently C 1-6 alkyl; and R 1 , X, and Z are as defined above in connection with Formula I.
  • B is:
  • R 2a and R 3a are each independently C 1-4 alkyl. In another embodiment, R 2a and R 3a are each methyl or ethyl.
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
  • R 3a and R 4a are each independently C 1-6 alkyl; or R 3a and R 4a taken together form a C 1-4 bridge; and R 1 , X, and Z are as defined above in connection with Formula I.
  • B is:
  • R 3a and R 4a are each independently C 1-4 alkyl. In another embodiment, R 3a and R 4a are each methyl or ethyl.
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is selected from the group consisting of:
  • B is selected from the rou consistin of:
  • B is selected from the rou consistin of:
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
  • R 2a and R 5a are each independently selected from the group consisting of C 1-6 alkyl and alkoxycarbonyl; or R 2a and R 5a taken together form a C 1-4 bridge; and R 1 , X, and Z are as defined above in connection with Formula I.
  • B is:
  • R 2a and R 5a are each independently selected from the group consisting of C 1-4 alkyl and alkoxycarbonyl. In another embodiment, R 2a and R 5a are each independently selected from the group consisting of methyl and -CO 2 Me.
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is absent and R 1 , B, and Z are as defined above in connection with Formula I.
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is selected from the group consisting of: ;
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is selected from the group consisting of:
  • Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (aralkylamino)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and optionally substituted C 3-12 cycloalkyl.
  • Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (aralkylamino)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to
  • Compounds of the Disclosure are compounds having Formula II:
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; or
  • R 2a and R 2b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 3a and R 3b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 4a and R 4b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 5a and R 5b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 2a and R 5a taken together form a C 1-4 bridge; and R 2b , R 3a , R 3b , R 4a , R 4b , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 3a and R 4a taken together form a C 1-4 bridge; and R 2a , R 2b , R 3b , R 4a , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R , R 3a , R 3b , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or [0073] R 3a and R 5a taken form a C 1-4 bridge; and R 2a , R 2b , R 3b , R 4a , R 4b , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;
  • R 6 is selected from the group consisting of hydrogen and C 1-4 alkyl
  • R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; or b) R 6 is C 1-4 alkyl; and
  • R 1 , X, and Z are as defined in connection with Formula I.
  • Compounds of the Disclosure are compounds having Formula II, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of optionally substituted C 1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C 3-12 cycloalkyl, aralkyl, and heteroaralkyl, when X is
  • Compounds of the Disclosure are compounds having Formula II, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; or
  • R 2a and R 2b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 3a and R 3b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
  • R 4a and R 4b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or [0083] R 5a and R 5b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; and
  • R 1 , R 6 , X, and Z are as defined in connection with Formula I.
  • Compounds of the Disclosure are compounds having Formula III:
  • Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, and optionally substituted 4- to 14-membered heterocyclo.
  • Compounds of the Disclosure are compounds having Formula IV:
  • Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, and optionally substituted 4- to 14-membered heterocyclo.
  • Compounds of the Disclosure are compounds having Formula V:
  • Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C 3-12 cycloalkyl. It will be understood by those of ordinary skill in the art that compounds having Formula V can be drawn in various ways, e.g.,
  • Compounds of the Disclosure are compounds having Formula VI:
  • Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C 3-12 cycloalkyl. It will be understood by those of ordinary skill in the art that compounds having Formula VI can be drawn in various ways, e.g.,
  • Compounds of the Disclosure are compounds having Formula VII:
  • Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C 3-12 cycloalkyl.
  • Compounds of the Disclosure are compounds having Formula VIII:
  • Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C 3-12 cycloalkyl.
  • Compounds of the Disclosure are compounds having Formula IX:
  • Compounds of the Disclosure are compounds having Formula X:
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is ethyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is ethyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is n-propyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is n-propyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is isopropyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is isopropyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is isobutyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is isobutyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is cyclopropyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is cyclopropyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is (heterocyclo)alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is a (heterocyclo)alkyl having the following structure: ;
  • R 12 is selected from the group consisting of hydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl.
  • R 12 is selected from the group consisting of hydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of:
  • Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is cyclopropyl and Z is selected from the group consisting of:
  • Compounds of the Disclosure are compounds of Table 1, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
  • the chemical names of the compounds of Table 1 are provided in Table 1A.
  • Compounds of the Disclosure are compounds of Table 2, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
  • the chemical names of the compounds of Table 2 are provided in Table 2A.
  • Compounds of the Disclosure are compounds of Table 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
  • the chemical names of the compounds of Table 3 are provided in Table 3A.
  • Compounds of the Disclosure are compounds of Tables 1 and 2, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
  • Compounds of the Disclosure are compounds of Tables 1, 2, and 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
  • Compounds of the Disclosure are compounds of Tables 1, 1A, 2, 2A, 3, and 3A, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
  • Compounds of the Disclosure are selected from the group consisting of:
  • a Compound of the Disclosure is a compound having Formulae I-X, provided that the compound is not:
  • compositions comprising one or more of the following compounds:
  • the disclosure relates to a method of inhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a subject, comprising administering to a subject in need thereof an effective amount of at least one of the following compounds:
  • alkyl refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C 1-12 alkyl) or the number of carbon atoms designated (i.e., a C 1 alkyl such as methyl, a C 2 alkyl such as ethyl, a C 3 alkyl such as propyl or isopropyl, etc.).
  • the alkyl group is chosen from a straight chain C 1-10 alkyl group.
  • the alkyl group is chosen from a branched chain C 3-10 alkyl group.
  • the alkyl group is chosen from a straight chain C 1-6 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C 3-6 alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C 1-4 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C 3-4 alkyl group. In another embodiment, the alkyl group is chosen from a straight or branched chain C 3-4 alkyl group. In another embodiment, the alkyl group is partially or completely deuterated, i.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms.
  • Non-limiting exemplary C 1-10 alkyl groups include methyl (including -CD 3 ), ethyl, propyl, isopropyl, butyl, sec-butyl, tert- butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • Non-limiting exemplary C 1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.
  • Non-limiting exemplary C 1-4 groups include methyl, ethyl, propyl, isopropyl, and tert-butyl.
  • the term "optionally substituted alkyl" as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, alkoxycarbonyl, and carboxyalkyl.
  • the alkyl is a C 1-4 alkyl.
  • the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent.
  • Non-limiting exemplary optionally substituted alkyl groups include -CH 2 CH 2 NO 2 , -CH 2 CH 2 CO 2 H, -CH 2 CH 2 SO 2 CH 3 , -CH 2 CH 2 COPh, and -CH 2 C 6 H 11 .
  • cycloalkyl refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C 3-12 cycloalkyl) or the number of carbons designated.
  • the cycloalkyl group has two rings.
  • the cycloalkyl group has one ring.
  • the cycloalkyl group is chosen from a C 3-8 cycloalkyl group.
  • the cycloalkyl group is chosen from a C 3-6 cycloalkyl group.
  • Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.
  • the term "optionally substituted cycloalkyl" as used by itself or as part of another group means that the cycloalkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkyny
  • the optionally substituted cycloalkyl is substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkyla
  • the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In one embodiment, the optionally substituted cycloalkyl is substituted with at least one amino, alkylamino, or dialkylamino group.
  • amino-substituted cycloalkyl as used by itself or as part of another group means that the optionally susbstituted cycloalkyl as defined above is substituted with at least one amino group. In one embodiment, the amino-substituted cycloalkyl is an amino-substituted cyclohexyl group.
  • Non-limiting exemplary optionally substituted cycloalkyl groups include:
  • cycloalkenyl as used by itself or part of another group refers to a partially unsaturated cycloalkyl group as defined above.
  • the cycloalkenyl has one carbon-to-carbon double bond.
  • the cycloalkenyl group is chosen from a C 4-8 cycloalkenyl group.
  • Exemplary cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
  • the term "optionally substituted cycloalkenyl" as used by itself or as part of another group means that the cycloalkenyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkyl, optionally substituted cycloalky
  • the optionally substituted cycloalkenyl is substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkyl,
  • the optionally substituted cycloalkenyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkenyl is substituted with one substituent. In another embodiment, the cycloalkenyl is unsubstituted.
  • alkenyl refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds.
  • the alkenyl group is chosen from a C 2-6 alkenyl group.
  • the alkenyl group is chosen from a C 2-4 alkenyl group.
  • Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
  • alkenyl as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted
  • alkynyl refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds.
  • the alkynyl has one carbon-to-carbon triple bond.
  • the alkynyl group is chosen from a C 2-6 alkynyl group.
  • the alkynyl group is chosen from a C 2-4 alkynyl group.
  • Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
  • the term "optionally substituted alkynyl" as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.
  • haloalkyl refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and/or iodine atoms.
  • the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms.
  • the haloalkyl group is chosen from a C 1-4 haloalkyl group.
  • Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.
  • fluoroalkyl as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine atoms.
  • the alkyl group is substituted by one, two, or three fluorine atoms.
  • the fluoroalkyl group is chosen from a C 1-4 fluoroalkyl group.
  • Non-limiting exemplary fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl.
  • hydroxyalkyl refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups.
  • the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxy group.
  • the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups.
  • the hydroxyalkyl group is chosen from a C 1-4 hydroxyalkyl group.
  • Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2- yl.
  • alkoxy refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom.
  • the alkoxy group is chosen from a C 1-4 alkoxy group.
  • the alkoxy group is chosen from a C 1-4 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, and tert-butoxy.
  • alkylthio refers to a sulfur atom substituted by an optionally substituted alkyl group.
  • the alkylthio group is chosen from a C 1-4 alkylthio group.
  • Non-limiting exemplary alkylthio groups include -SCH 3 , and -SCH 2 CH 3 .
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group.
  • Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.
  • haloalkoxy as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom.
  • Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
  • heteroalkyl refers to a stable straight or branched chain hydrocarbon radical containing 1 to 10 carbon atoms and at least two heteroatoms, which can be the same or different, selected from O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) can optionally be oxidized; and/or 2) the nitrogen atom(s) can optionally be quaternized.
  • the heteroatoms can be placed at any interior position of the heteroalkyl group or at a position at which the heteroalkyl group is attached to the remainder of the molecule.
  • the heteroalkyl group contains two oxygen atoms.
  • the heteroalkyl contains one oxygen and one nitrogen atom. In one embodiment, the heteroalkyl contains two nitrogen atoms.
  • Non-limiting exemplary heteroalkyl groups include -CH 2 OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH 2 NHCH 2 CH 2 OCH 2 , -OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 N(H)CH 3 , -CH 2 CH 2 CH 2 N(H)CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 N(H)CH 2 CH 2 N(H)CH 3 , -NHCH 2 CH 2 OCH 3, -N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , and -OCH 2 CH 2 OCH 3 .
  • aryl refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms (i.e., C 6-14 aryl).
  • Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups.
  • the aryl group is chosen from phenyl or naphthyl.
  • the aryl group is phenyl.
  • the term "optionally substituted aryl" as used herein by itself or as part of another group means that the aryl as defined above is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkenyl, alkenyl, alky
  • the optionally substituted aryl is substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,
  • the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. In another embodiment, the optionally substituted phenyl has at least one amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl substituent.
  • (amino)alkyl-substituted phenyl as used by itself or as part of another group means that the optionally susbstituted phenyl as defined above is substituted with at least one (amino)alkyl group.
  • Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di- methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, 2-phenylpropan-2- amine,
  • optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include: .
  • aryloxy as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom.
  • a non-limiting exemplary aryloxy group is PhO-.
  • heteroaryloxy refers to an optionally substituted heteroaryl attached to a terminal oxygen atom.
  • aralkyloxy or "arylalkyloxy” as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom.
  • a non-limiting exemplary aralkyloxy group is PhCH 2 O-.
  • heteroaryl refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms (i.e., a 5- to 14-membered heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen or sulfur.
  • the heteroaryl has three heteroatoms.
  • the heteroaryl has two heteroatoms.
  • the heteroaryl has one heteroatom.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom.
  • the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom.
  • Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, ⁇ -carboliny
  • the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H- imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2- yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g.
  • the term "optionally substituted heteroaryl" as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkyny
  • the optionally substituted heteroaryl is substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkyl,
  • the optionally substituted heteroaryl has one substituent.
  • the optionally substituted is an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can be substituted.
  • heterocycle or “heterocyclo” as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members (i.e., a 3- to 14-membered heterocyclo) and at least one heteroatom.
  • Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be quaternized.
  • heterocyclo is meant to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as ⁇ -lactam, ⁇ -lactam, ⁇ - lactam and ⁇ -lactam, and cyclic carbamate groups such as oxazolidinyl-2-one.
  • heterocyclo is also meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl, indolinyl-2-one, benzo[d]oxazolyl-2(3H)-one.
  • the heterocyclo group is chosen from a 4-, 5-, 6-, 7- or 8-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 8-, 9-, 10-, 11-, or 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.
  • Non-limiting exemplary heterocyclo groups include 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, 8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6-azaspiro[3.4]octane, indolinyl, indolinyl-2-one, 1,3-dihydro-2H-benzo[d]imidazol-2- one.
  • the term "optionally substituted heterocyclo" as used herein by itself or part of another group means the heterocyclo as defined above is either unsubstituted or substituted with one to four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally
  • Substitution may occur on any available carbon or nitrogen atom, and may form a spirocycle.
  • the optionally substituted heterocyclo is substituted with one to four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)al
  • the optionally substituted heterocyclo is substituted with at least one amino, alkylamino, or dialkylamino group.
  • amino-substituted heterocyclo as used by itself or as part of another group means that the optionally susbstituted heterocyclo as defined above is substituted with at least one amino group.
  • alkylamino-substituted heterocyclo as used by itself or as part of another group means that the optionally susbstituted heterocyclo as defined above is substituted with at least one alkylamino group.
  • the amino-substituted or alkylamino- substituted heterocyclo is an amino-substituted or alkylamino-substituted piperidine.
  • Non-limiting exemplary optionally substituted heterocyclo groups include:
  • amino as used by itself or as part of another group refers to -NH 2 .
  • alkylamino as used by itself or as part of another group refers to -NHR 22 , wherein R 22 is C 1-6 alkyl. In one embodiment, R 22 is C 1-4 alkyl.
  • Non-limiting exemplary alkylamino groups include -N(H)CH 3 and -N(H)CH 2 CH 3 .
  • dialkylamino as used by itself or as part of another group refers to -NR 23a R 23b , wherein R 23a and R 23b are each independently C 1-6 alkyl. In one embodiment, R 23a and R 23b are each independently C 1-4 alkyl.
  • Non-limiting exemplary dialkylamino groups include -N(CH 3 ) 2 and -N(CH 3 )CH 2 CH(CH 3 ) 2 .
  • hydroxyalkylamino as used by itself or as part of another group refers to -NHR 24 , wherein R 24 is hydroxyalkyl.
  • cycloalkylamino as used by itself or as part of another group refers to -NR 25a R 25b , wherein R 25a is optionally substituted cycloalkyl and R 25b is hydrogen or C 1-4 alkyl.
  • aralkylamino as used by itself or as part of another group refers to -NR 26a R 26b , wherein R 26a is aralkyl and R 26b is hydrogen or C 1-4 alkyl.
  • Non-limiting exemplary aralkylamino groups include -N(H)CH 2 Ph, -N(H)CHPh 2 , and -N(CH 3 )CH 2 Ph.
  • (cycloalkyl)alkylamino refers to -NR 26c R 26d , wherein R 26c is (cycloalkyl)alkyl and R 26d is hydrogen or C 1-4 alkyl.
  • Non-limiting exemplary (cycloalkyl)alkylamino groups include: .
  • (heterocyclo)alkylamino refers to -NR 26e R 26f , wherein R 26e is (heterocyclo)alkyl and R 26f is hydrogen or C 1-4 alkyl.
  • Non-limiting exemplary (heterocyclo)alky .
  • (amino)alkyl refers to an alkyl group substituted with an amino group.
  • the alkyl is a C 1-4 alkyl.
  • Non-limiting exemplary (amino)alkyl groups include -CH 2 NH 2 , -C(CH 3 )NH 2 , -C(NH 2 )(H)CH 3 , -CH 2 CH 2 NH 2 , -CH 2 C(NH 2 )(H)CH 3 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , and -CH 2 C(CH 3 ) 2 CH 2 NH 2 .
  • (alkylamino)alkyl refers to an alkyl group substituted with an alkylamino group.
  • the alkyl is a C 1-4 alkyl.
  • a non-limiting exemplary (alkylamino)alkyl group is -CH 2 CH 2 N(H)CH 3 .
  • dialkylamino)alkyl refers to an alkyl group substituted by a dialkylamino group.
  • the alkyl is a C 1-4 alkyl.
  • Non-limiting exemplary (dialkylamino)alkyl groups are -CH 2 CH 2 N(CH 3 ) 2 .
  • (cycloalkylamino)alkyl refers to an alkyl group substituted by a cycloalkylamino group.
  • the alkyl is a C 1-4 alkyl.
  • Non-limiting exemplary (cycloalkylamino)alkyl groups include -CH 2 N(H)cyclopropyl, -CH 2 N(H)cyclobutyl, and -CH 2 N(H)cyclohexyl.
  • the term "[(cycloalkyl)alkylamino]alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a (cycloalkyl)alkylamino group.
  • the alkyl is a C 1-4 alkyl.
  • Non-limiting exemplary ([(cycloalkyl)alkylamino]alkyl groups include:
  • the term "[(heterocyclo)alkylamino]alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a (heterocyclo)alkylamino group.
  • the alkyl is a C 1-4 alkyl.
  • Non-limiting exemplary ([(heterocyclo)alkylamino]alkyl groups include: .
  • (aralkylamino)alkyl refers to an alkyl group substituted with an aralkylamino group.
  • the alkyl is a C 1-4 alkyl.
  • Non-limiting exemplary (aralkylamino)alkyl groups include -CH 2 CH 2 CH 2 N(H)CH 2 Ph and -CH 2 CH 2 CH 2 N(H)CH 2 (4-CF 3 -Ph).
  • (cyano)alkyl refers to an alkyl group substituted with one or more cyano, e.g., -CN, groups.
  • the alkyl is a C 1-4 alkyl.
  • Non-limiting exemplary (cyano)alkyl groups include -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, and -CH 2 CH 2 CH 2 CH 2 CN.
  • (amino)(hydroxy)alkyl refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one hydroxy group.
  • the alkyl is a C 1-6 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • Non-limiting exemplary (amino)(hydroxy)alkyl groups include:
  • (amino)(aryl)alkyl refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one optionally substituted aryl group.
  • the alkyl is a C 1-6 alkyl.
  • the optionally substituted aryl group is an optionally substituted phenyl.
  • (cycloalkyl)alkyl refers to an alkyl group substituted with one optionally substituted cycloalkyl group.
  • the alkyl is a C 1-4 alkyl.
  • the cycloalkyl is a C 3-6 cycloalkyl.
  • the optionally substituted cycloalkyl group is substituted with an amino or (amino)alkyl group.
  • Non-limiting exemplary (cycloalkyl)alkyl groups include:
  • (hydroxy)(aryl)alkyl refers to an alkyl group substituted with one hydroxy group and one optionally substituted aryl group.
  • the alkyl is a C 1-6 alkyl.
  • the optionally substituted aryl group is an optionally substituted phenyl.
  • Non-limiting exemplary (hydroxy)(aryl)alkyl groups include: .
  • Non-limiting exemplary carboxamido groups include -CONH 2 , -CON(H)CH 3 , CON(CH 3 ) 2 , and -CON(H)Ph.
  • (carboxamido)alkyl refers to an alkyl group substituted with a carboxamido group.
  • Non-limiting exemplary (carboxamido)alkyl groups include -CH 2 CONH 2 , -C(H)CH 3 -CONH 2 , and -CH 2 CON(H)CH 3 .
  • sulfonamido refers to a radical of the formula -SO 2 NR 27a R 27b , wherein R 27a and R 27b are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R 27a and R 27b taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group.
  • Non-limiting exemplary sulfonamido groups include -SO 2 NH 2 , -SO 2 N(H)CH 3 , and -SO 2 N(H)Ph.
  • a non-limiting exemplary alkylcarbonyl group is -COCH 3 .
  • a non-limiting exemplary arylcarbonyl group is -COPh.
  • alkylsulfonyl as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO 2 -, substituted by any of the above-mentioned optionally substituted alkyl groups.
  • a non-limiting exemplary alkylsulfonyl group is -SO 2 CH 3 .
  • arylsulfonyl as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO 2 -, substituted by any of the above-mentioned optionally substituted aryl groups.
  • a non-limiting exemplary arylsulfonyl group is -SO 2 Ph.
  • mercaptoalkyl as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a–SH group.
  • carboxy as used by itself or as part of another group refers to a radical of the formula -COOH.
  • carboxyalkyl as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a -COOH.
  • a non-limiting exemplary carboxyalkyl group is -CH 2 CO 2 H.
  • the alkoxy group is a C 1-4 alkoxy.
  • Non-limiting exemplary alkoxycarbonyl groups are -CO 2 Me and -CO 2 Et.
  • aralkyl or “arylalkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups.
  • the aralkyl group is a C 1-4 alkyl substituted with one optionally substituted aryl group.
  • Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh 2 , -CH 2 (4-OH-Ph), and -CH(4-F-Ph) 2 .
  • the term "(heterocyclo)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclo groups.
  • the (heterocyclo)alkyl is a C 1-4 alkyl substituted with one optionally substituted heterocyclo group.
  • the heterocyclo can be linked to the alkyl group through a carbon or nitrogen atom.
  • Non-limiting exemplary (heterocyclo)alkyl groups include:
  • the term "(heteroaryl)alkyl” or “heteroaralkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups.
  • the (heteroaryl)alkyl group is a C 1-4 alkyl substituted with one optionally substituted heteroaryl group.
  • Non-limiting exemplary (heteroaryl)alkyl groups include: , .
  • alkylcarbonylamino refers to an alkylcarbonyl group attached to an amino.
  • a non-limiting exemplary alkylcarbonylamino group is -NHCOCH 3 .
  • C 1-4 bridge refers to a -CH 2 -, -(CH 2 ) 2 - , -(CH 2 ) 3 -, or -(CH 2 ) 4 - group that joins two carbon atoms of a piperidine to form an azabicyclo group.
  • R 3a and R 4a of B can be taken together to form a 6-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, or 10-azabicyclo[4.3.1]decane group.
  • Each methylene unit of the C 1-4 bridge can be optionally substituted with one or two substituents independently selected from the group consisting of C 1-4 alkyl and halo.
  • the present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H (or deuterium (D)), 3 H, 1 1 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively, e.g., 3 H, 11 C, and 14 C.
  • compositions wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number.
  • Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.
  • Compounds of the Disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • the present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof.
  • the individual enantiomers can be separated according to methods known in the art in view of the present disclosure.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.
  • stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers). [0200]
  • chiral center or “asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.
  • enantiomer and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
  • racemic refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
  • Compounds of the Disclosure are racemic.
  • absolute configuration refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.
  • enantiomeric excess refers to a measure for how much of one enantiomer is present compared to the other.
  • the percent enantiomeric excess is defined as ([D] obs /[D] max )*100, where [D] obs is the optical rotation of the mixture of enantiomers and [D] max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.
  • enantiomerically pure or “enantiopure” refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense.
  • Compounds of the Disclosure are enantiomerically pure.
  • enantiomerically enriched or “enantioenriched” refer to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50.
  • Compounds of the Disclosure are enantiomerically enriched, e.g., the enantiomeric ratio is about 60:40 or greater, about 70:30 or greater, about 80:20 or greater, about 90:10 or greater, about 95:5 or greater, about 98:2 or greater, or about 99:1 or greater.
  • Enantiomerically enriched compounds may be enantiomerically pure.
  • the present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts.
  • pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts.
  • the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the
  • pharmaceutically acceptable salt refers to any salt, e.g., obtained by reaction with an acid or a base, of a Compound of the Disclosure that is physiologically tolerated in the target patient (e.g., a mammal, e.g., a human).
  • Acid addition salts can be formed by mixing a solution of the particular Compound of the Disclosure with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or the like.
  • Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
  • solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents.
  • solvate as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively.
  • This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
  • solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • solvate encompasses both solution-phase and isolatable solvates.
  • Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure.
  • a pharmaceutically acceptable solvent such as water, methanol, ethanol, and the like
  • solvate is a hydrate.
  • a "hydrate” relates to a particular subgroup of solvates where the solvent molecule is water.
  • Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M.
  • a typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration.
  • Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.
  • Compounds of the Disclosure are inhibitors of SMYD proteins, such as SMYD3 and SMYD2, a number of diseases, conditions, or disorders mediated by SMYD proteins, such as SMYD3 and SMYD2, can be treated by employing these compounds.
  • the present disclosure is thus directed generally to a method for treating a disease, condition, or disorder responsive to the inhibition of SMYD proteins, such as SMYD3 and SMYD2, in an animal suffering from, or at risk of suffering from, the disorder, the method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.
  • the present disclosure is further directed to a method of inhibiting SMYD proteins in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
  • the present disclosure is further directed to a method of inhibiting SMYD3 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
  • the present disclosure is further directed to a method of inhibiting SMYD2 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
  • the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
  • the terms “treat,” “treating,” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
  • the term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need of such treatment.
  • treatment also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
  • the treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
  • terapéuticaally effective amount refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to an individual in need thereof.
  • the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; modulate protein methylation in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer.
  • the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
  • the term "container” means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
  • insert means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product.
  • the package insert generally is regarded as the "label" for a pharmaceutical product.
  • SMYD proteins such as SMYD3 and SMYD2
  • SMYD3 and SMYD2 can be used in treating diseases and conditions such as proliferative diseases, wherein inhibition of SMYD proteins, such as SMYD3 and SMYD2 provides a benefit.
  • the Compounds of the Disclosure can be used to treat a "SMYD protein mediated disorder" (e.g., a SMYD3-mediated disorder or a SMYD2-mediated disorder).
  • a SMYD protein mediated disorder is any pathological condition in which a SMYD protein is know to play a role.
  • a SMYD-mediated disorder is a proliferative disease.
  • inhibiting SMYD proteins is the inhibition of the activity of one or more activities of SMYD proteins such as SMYD3 and SMYD2.
  • the activity of the SMYD proteins such as SMYD3 and SMYD2 is the ability of the SMYD protein such as SMYD3 or SMYD2 to transfer a methyl group to a target protein (e.g., histone). It should be appreciated that the activity of the one or more SMYD proteins such as SMYD3 and SMYD2 may be inhibited in vitro or in vivo.
  • Examplary levels of inhibition of the activity one or more SMYD proteins such as SMYD3 and SMYD2 include at least 10% inhibition, at least 20% inhibition, at least 30% inhibition, at least 40% inhibition, at least 50% inhibition, at least 60% inhibition, at least 70% inhibition, at least 80% inhibition, at least 90% inhibition, and up to 100% inhibition.
  • the SMYD (SET and MYND domain) family of lysine methyltransferases (KMTs) plays pivotal roles in various cellular processes, including gene expression regulation and DNA damage response.
  • the family of human SMYD proteins consists of SMYD1, SMYD2, SMYD3, SMYD4 and SMYD5.
  • SMYD1, SMYD2, and SMYD3 share a high degree of sequence homology and, with the exception of SMYD5, human SMYD proteins harbor at least one C-terminal tetratrico peptide repeat (TPR) domain.
  • TPR tetratrico peptide repeat
  • SMYD3 is a protein methyltransferase found to be expressed at high levels in a number of different cancers (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004)). SMYD3 likely plays a role in the regulation of gene transcription and signal transduction pathways critical for survival of breast, liver, prostate and lung cancer cell lines (Hamamoto, R., et al., Nat.
  • RNAi-based technologies have shown that ablation of SMYD3 in hepatocellular carcinoma cell lines greatly reduces cell viability and that its pro-survival role is dependent on its catalytic activity (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Van Aller, G.S., et al., Epigenetics, 7(4):340-3 (2012)).
  • SMYD3 has also been shown to be a critical mediator of transformation resulting from gain of function mutations in the oncogene, KRAS for both pancreatic and lung adenocarcinoma in mouse models.
  • SMYD3 function has also been shown to play a role in immunology and development. For instance, de Almeida reported that SMYD3 plays a role in generation of inducible regulatory T cells (iTreg) cells.
  • iTreg inducible regulatory T cells
  • SMYD3-/- mice demonstrated exacerbation of RSV- induced disease related to enhanced proinflammatory responses and worsened pathogenesis within the lung (de Almeida et al. Mucosal Immunol. 2015 Feb 11. doi: 10.1038/mi.2015.4. [Epub ahead of print]).
  • SMYD2 (SET and MYND domain-containing protein 2) was first characterized as protein that is a member of a sub-family of SET domain containing proteins which catalyze the site-specific transfer of methyl groups onto substrate proteins.
  • SMYD2 was initially shown to have methyltransferase activity towards lysine 36 on histone H3 (H3K36) but has subsequently been shown to have both histone and non-histone methyltrasferase activity.
  • SMYD2 has been implicated in the pathogenesis of multiple cancers. It has been shown to be over-expressed, compared to matched normal samples, in tumors of the breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus and prostate, as well as hematologic malignancies such as AML, B- and T-ALL, CLL and MCL, suggesting a role for SMYD2 in the biology of these cancers. More specifically, studies using genetic knock-down of SMYD2 have demonstrated anti-proliferative effects in esophageal squamous cell carcinoma (ESCC), bladder carcinoma and cervical carcinoma cell lines.
  • ESCC esophageal squamous cell carcinoma
  • SMYD2 has also been implicated in immunology. For instance, Xu et al. have shown that SMYD2 is a negative regulator of macrophage activation by suppressing Interleukin-6 and TNF-alpha production. (Xu et al., J Biol Chem. 2015 Feb 27;290(9):5414-23).
  • the present disclosure provides a method of treating cancer in a patient comprising administering a therapeutically effective amount of a Compound of the Disclosure. While not being limited to a specific mechanism, in some embodiemtns, Compounds of the Disclorure can treat cancer by inhibiting SMYD proteins, such as SMYD3 and SMYD2.
  • treatable cancers include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell
  • the cancer is breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus, or prostate cancer.
  • the cancer is a hematologic malignancy such as acute myeloid leukemia (AML), B- and T-acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma (MCL).
  • AML acute myeloid leukemia
  • ALL B- and T-acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • the cancer is esophageal squamous cell carcinoma (ESCC), bladder carcinoma, or cervical carcinoma.
  • ESCC esophageal squamous cell carcinoma
  • bladder carcinoma esophageal squamous cell carcinoma
  • cervical carcinoma esophageal squamous cell carcinoma
  • the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL).
  • the cancer is NUT-midline carcinoma.
  • the cancer is multiple myeloma.
  • the cancer is a lung cancer such as small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • the cancer is a neuroblastoma.
  • the cancer is Burkitt's lymphoma.
  • the cancer is cervical cancer.
  • the cancer is esophageal cancer.
  • the cancer is ovarian cancer.
  • the cancer is colorectal cancer.
  • the cancer is prostate cancer.
  • the cancer is breast cancer.
  • the present disclosure provides a therapeutic method of modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in the cancers mentioned above by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such therapy.
  • Compounds of the Disclosure can be administered to a mammal in the form of a raw chemical without any other components present.
  • Compounds of the Disclosure can also be administered to a mammal as part of a pharmaceutical composition containing the compound combined with a suitable pharmaceutically acceptable carrier.
  • a suitable pharmaceutically acceptable carrier can be selected from pharmaceutically acceptable excipients and auxiliaries.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable vehicle” encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.
  • compositions within the scope of the present disclosure include all compositions where a Compound of the Disclosure is combined with one or more pharmaceutically acceptable carriers.
  • the Compound of the Disclosure is present in the composition in an amount that is effective to achieve its intended therapeutic purpose. While individual needs may vary, a determination of optimal ranges of effective amounts of each compound is within the skill of the art.
  • a Compound of the Disclosure can be administered to a mammal, e.g., a human, orally at a dose of from about 0.0025 to about 1500 mg per kg body weight of the mammal, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, per day to treat the particular disorder.
  • a useful oral dose of a Compound of the Disclosure administered to a mammal is from about 0.0025 to about 50 mg per kg body weight of the mammal, or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof.
  • the dose is typically about one-half of the oral dose.
  • a unit oral dose may comprise from about 0.01 mg to about 1 g of the Compound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about 50 mg, e.g., about 0.1 mg to about 10 mg, of the compound.
  • the unit dose can be administered one or more times daily, e.g., as one or more tablets or capsules, each containing from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition of the present disclosure can be administered to any patient that may experience the beneficial effects of a Compound of the Disclosure.
  • mammals e.g., humans and companion animals, although the disclosure is not intended to be so limited.
  • the patient is a human.
  • a pharmaceutical composition of the present disclosure can be administered by any means that achieves its intended purpose.
  • administration can be by the oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or buccal route, or by inhalation.
  • the dosage administered and route of administration will vary, depending upon the circumstances of the particular subject, and taking into account such factors as age, gender, health, and weight of the recipient, condition or disorder to be treated, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • a pharmaceutical composition of the present disclosure can be administered orally.
  • a pharmaceutical composition of the present disclosure can be administered orally and is formulated into tablets, dragees, capsules, or an oral liquid preparation.
  • the oral formulation comprises extruded multiparticulates comprising the Compound of the Disclosure.
  • a pharmaceutical composition of the present disclosure can be administered rectally, and is formulated in suppositories.
  • composition of the present disclosure can be administered by injection.
  • composition of the present disclosure can be administered transdermally.
  • composition of the present disclosure can be administered by inhalation or by intranasal or transmucosal administration.
  • composition of the present disclosure can be administered by the intravaginal route.
  • a pharmaceutical composition of the present disclosure can contain from about 0.01 to 99 percent by weight, e.g., from about 0.25 to 75 percent by weight, of a Compound of the Disclosure, e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a Compound of the Disclosure.
  • a Compound of the Disclosure e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a Compound of the Disclosure.
  • a pharmaceutical composition of the present disclosure is manufactured in a manner which itself will be known in view of the instant disclosure, for example, by means of conventional mixing, granulating, dragee-making, dissolving, extrusion, or lyophilizing processes.
  • pharmaceutical compositions for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • saccharides for example, lactose, sucrose, mannitol or sorbitol
  • cellulose preparations for example, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate)
  • binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl
  • one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and polyethylene glycol.
  • Dragee cores are provided with suitable coatings that are resistant to gastric juices.
  • concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate
  • Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Examples of other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, or soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain a compound in the form of granules, which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers, or in the form of extruded multiparticulates.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin.
  • stabilizers can be added.
  • Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base.
  • Suitable suppository bases include natural and synthetic triglycerides, and paraffin hydrocarbons, among others. It is also possible to use gelatin rectal capsules consisting of a combination of active compound with a base material such as, for example, a liquid triglyceride, polyethylene glycol, or paraffin hydrocarbon.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compound in a water-soluble form such as, for example, a water-soluble salt, alkaline solution, or acidic solution.
  • a suspension of the active compound can be prepared as an oily suspension.
  • Suitable lipophilic solvents or vehicles for such as suspension may include fatty oils (for example, sesame oil), synthetic fatty acid esters (for example, ethyl oleate), triglycerides, or a polyethylene glycol such as polyethylene glycol-400 (PEG-400).
  • An aqueous suspension may contain one or more substances to increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may optionally contain stabilizers.
  • kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure.
  • the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure.
  • the compound or composition is packaged in a unit dosage form.
  • the kit further can include a device suitable for administering the composition according to the intended route of administration.
  • a suitable sulfonyl chloride Z-SO 2 Cl
  • a suitable acide chloride Z-COCl
  • a suitable base such as TEA or DIPEA
  • a suitable solvent such as dichloromethane, acetonitrile, or DMF
  • a suitable coupling reagent such as HATU and a suitable base such as TEA or DIPEA
  • a suitable solvent such as dichloromethane, acetonitrile, or DMF.
  • Step 1 Synthesis of ethyl 4-cyclopropyl-2,4-dioxobutanoate
  • Step 2 Synthesis of ethyl 5-cyclopropylisoxazole-3-carboxylate
  • Step 2 Synthesis of (2S)-tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-2- methylpiperidine-1-carboxylate
  • Step 3 Synthesis of tert-butyl (2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidine-1-carboxylate and tert-butyl (2S,4R)-4-(5-cyclopropyl-1,2-oxazole-3- amido)-2-methylpiperidine-1-carboxylate
  • Step 4 Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole- 3-carboxamide hydrochloride and 5-cyclopropyl-N-((2S,4R)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide hydrochloride
  • Step 2 Synthesis of (2R,4R)-tert-butyl 4-(5-cyclopropylisoxazole-3- carboxamido)-2-methylpiperidine-1-carboxylate and (2R,4S)-tert-butyl 4-(5- cyclopropylisoxazole-3-carboxamido -2-meth l i eridine-1-carbox late
  • Prep-SFC 350 Column, CHIRALPAK AD-H SFC, 5x25cm,5um; mobile phase, CO 2 (50%), methanol(50%); Detector, uv 220nm. This was resulted in 7.48 g (54%) of tert-butyl (2R,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate as light yellow oil.
  • Step 3 Synthesis of 5-cyclopropyl-N-((2R,4R)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide h drochloride
  • Step 4 Synthesis of 5-cyclopropyl-N-((2R,4S)-2-methylpiperidin-4-yl)isoxazole- 3-carboxamide hydrochloride
  • Step 1 Synthesis of tert-butyl 4-amino-2-benzylpiperidine-1-carboxylate
  • the resulting mixture was concentrated under vacuum.
  • the resulting solution was diluted with 200 mL of EA.
  • the resulting mixture was washed with 3x200 mL of brine (sat.).
  • the organic phase was collected and dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). The collected fractions were combined and concentrated under vacuum.
  • the trans mixture was purified by Prep-SFC with the following conditions (prep SFC 350): Column, Phenomenex Lux 5u Cellulose-4250*50mm00G-4491-V0- AX664184-1; mobile phase, CO 2 (50%) and MeOH(50%) ,Detector, uv 220 nm.
  • Step 3 Synthesis of N-((2R,4R)-2-benzylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide h drochloride
  • Step 1 Synthesis of (1R,5S,E)-tert-butyl 3-(hydroxyimino)-9- azabicyclo[3.3.1]nonane-9-carboxylate
  • Step 2 Synthesis of (1R,3s,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9- carboxylate and (1R,3r,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate
  • Step 3 Synthesis of (1R,3s,5S)-tert-butyl 3-(5-cyclopropylisoxazole-3- carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate and (1R,3r,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate
  • the resulting solution was stirred for 3 h at room temperature.
  • the resulting solution was diluted with 400 mL of DCM.
  • the resulting mixture was washed with 2x400 mL of H 2 O.
  • the residue was purified on a silica gel column with dichloromethane/methanol (20:1).
  • Step 4 Synthesis of (1R,3s,5S)-tert-butyl 3-(5-cyclopropylisoxazole-3- carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate and (1R,3r,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate
  • Step 5 Synthesis of N-((1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5- cyclopropylisoxazole-3-carboxamide
  • Step 6 Synthesis of N-((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5- cyclopropylisoxazole-3-carboxamide
  • (1R,3s,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate 8.0 g, 21.25 mmol, 1.00 equiv
  • dichloromethane 100 mL
  • Step 1 Synthesis of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate [0291] Into a 2000-mL 3-necked round-bottom flask was placed HCOONH 4 (42 g, 666.03 mmol, 30.00 equiv), acetic acid (1.3 g, 21.65 mmol, 1.00 equiv) and methanol (1.5 L). Then NaBH 3 CN (2.8 g, 44.56mmol, 2.00 equiv) was added into batch wise.
  • Step 2 Synthesis of tert-butyl (1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3- amido)-8-azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,3s,5S)-3-(5- cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylate
  • Step 3 Sytnthesis of N-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide hydrochloride and N-((1R,3s,5S)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride
  • Step 1 Synthesis of ethyl (2E)-2-cyano-3-(4-hydroxyphenyl)prop-2-enoate
  • Step 2 Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[(4- hydroxyphenyl)methyl] propanoate
  • Step 3 Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxy-3- iodophenyl)methyl]propanoate
  • Step 4 Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3- (prop-1-en-2-yl)phenyl]methyl]propanoate
  • the resulting solution was stirred overnight at 100 o C.
  • the resulting solution was diluted with 40 mL of NH 4 Cl (sat. aq.).
  • the resulting solution was extracted with 4x40 mL of ethyl acetate and the organic layers combined.
  • the resulting mixture was washed with 4x50 mL of NH 4 Cl (sat. aq.).
  • the resulting mixture was concentrated under vacuum.
  • the residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:5).
  • Step 5 Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3- (propan-yl)phenyl]methyl]propanoate
  • Step 6 Synthesis of 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan- 2-yl)phenyl]methyl]propanoic acid
  • Step 7 Synthesis of tert-butyl N-[3-[4-(5-cyclopropyl-1,2-oxazole-3- amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3- oxopropyl]carbamate
  • Step 8 Synthesis of tert-butyl N-[(2S)-3-[4-(5-cyclopropyl-1,2-oxazole-3- amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3- oxopropyl]carbamate
  • Step 9 Synthesis of N-[1-[(2S)-3-Amino-2-[[4-hydroxy-3-(propan-2- yl)phenyl]methyl] propanoyl]piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride salt
  • Step 1 Synthesis of tert-butyl 2,5-dimethylpyridin-4-ylcarbamate
  • Step 2 Synthesis of tert-butyl 2,5-dimethylpiperidin-4-ylcarbamate
  • Step 3 Synthesis of tert-butyl 1-((1R,4R)-4-(1,3-dioxoisoindolin-2- yl)cyclohexanecarbonyl) -2,5-dimethylpiperidin-4-ylcarbamate
  • Step 4 Synthesis of 2-((1R,4R)-4-(4-Amino-2,5-dimethylpiperidine-1- carbonyl)cyclohexyl) isoindoline-1,3-dione h drochloride
  • Step 5 Synthesis of 5-Cyclopropyl-N-(1-((1R,4R)-4-(1,3-dioxoisoindolin-2- yl)cyclohexanecarbonyl)-2,5-dimethylpiperidin-4-yl)isoxazole-3-carboxamide
  • Step 7 Synthesis of N-((2R,4S,5R)-1-((1r,4R)-4-Aminocyclohexanecarbonyl)- 2,5-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
  • Step 1 Synthesis of tert-butyl 4-amino-3-methylpiperidine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-3- methylpiperidine-1-carboxylate
  • the resulting solution was diluted with 50 mL of H 2 O.
  • the resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined.
  • the resulting mixture was washed with 3x150 mL of brine (sat.).
  • the mixture was dried over anhydrous sodium sulfate.
  • the residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 6 g (52%) of tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-3- methylpiperidine-1-carboxylateas yellow solid.
  • Step 3 Synthesis of (3S,4R)-tert-butyl 4-(5-cyclopropylisoxazole-3- carboxamido)-3-methylpi eridine-1-carbox late
  • Step 4 Synthesis of 5-cyclopropyl-N-((3S,4R)-3-methylpiperidin-4-yl)isoxazole- 3-carboxamide
  • Step 5 Synthesis of 5-cyclopropyl-N-((3S,4R)-1-(3-(1,3-dioxoisoindolin-2- yl)propylsulfonyl)-3-meth l i eridin-4- l isoxazole-3-carboxamide
  • Step 6 Synthesis of N-((3S,4R)-1-(3-aminopropylsulfonyl)-3-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide
  • the crude product (100 mg) was purified by Prep-HPLC with the following conditions : Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A:Water/NH 4 HCO 3 10mmol, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 30%B to 85%B in 10 min; Detector,254nm This resulted in 66.4 mg (30%) of N-[(3R,4S)-1-[(3- aminopropane)sulfonyl]-3-methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3- carboxamide as a white solid.
  • Step 1 Synthesis of 5-cyclopropyl-N-(9-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol- 2-yl)propane]sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl)-1,2-oxazole-3-carboxamide
  • Step 2 Synthesis of N-[9-[(3-aminopropane)sulfonyl]-9-azabicyclo[3.3.1]nonan- 3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride salt
  • Step 1 Synthesis of tert-butyl 4-[2-[(2S,4S)-2-benzyl-4-(5-cyclopropyl-1,2- oxazole-3-amido)pi eridin-1- l -2-oxoeth l i eridine-1-carbox late
  • Step 2 Synthesis of N-((2S,4S)-2-benzyl-1-(2-(piperidin-4-yl)acetyl)piperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride
  • Step 1 Synthesis of N-((1R,3r,5S)-8-(3-chloropropylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide
  • Step 2 Synthesis of 5-cyclopropyl-N-((1S,3r,5R)-8-(3-(1,3-dioxoisoindolin-2- yl)propylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide
  • Step 3 Synthesis of N-((1S,3r,5R)-8-(3-aminopropylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide
  • Step 1 Synthesis of 5-cyclopropyl-N-((1R,3s,5S)-8-(vinylsulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide
  • Step 2 Synthesis of 5-cyclopropyl-N-((1R,3s,5S)-8-((2-(pyrrolidin-1- yl)ethyl)sulfonyl)-8-azabicyclo 3.2.1 octan-3- l isoxazole-3-carboxamide
  • the crude product (89mg) was purified by Prep-HPLC with the following conditions(1#- Waters 2767-1): Column, X-bridge Prep phenyl 5um,19*150mmh Prep C012(T)186003581138241113.01; mobile phase, Phase A:water with 0.5% NH 4 HCO 3 ,Phase B:CH 3 CN .Water with 0.5% NH 4 HCO 3 and CH 3 CN (80% CH 3 CN up to 95% in 13 min ,hold 95% in 1min ,down to 80% in 1 min); Detector, uv254nm.
  • Step 3 Synthesis of (2S,4S)-tert-butyl 4-(5-cyclopropylisoxazole-3- carboxamido)-2-methylpiperidine-1-carboxylate
  • the diastereomeric product was further purified by Chiral-HPLC with the following conditions: Column name: CHIRALPAK AD-H, 4.6*150mm,5um,Co-Solvent: EtOH(0.1%DEA), %Co-Solvent: Hexane,25.000, Detector: 220nm.
  • the resulting solution was concentrated under vacuum. This resulted in 9.8 g (70%) of tert-butyl (2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate as colorless oil.
  • Step 4 Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole- 3-carboxamide hydrochloride
  • Step 5 Synthesis of N-((2S,4S)-1-(3-chloropropylsulfonyl)-2-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide
  • Step 6 Synthesis of N-((2S,4S)-1-(3-(benzylamino)propylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
  • Step 1 Synthesis of N-((2S,4S)-1-(6-chloropyridin-3-ylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
  • Step 2 Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(6-(2- morpholinoethylamino) pyridin-3-ylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide dihydrochloride
  • Step 1 Synthesis of tert-butyl 4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidine-1-carboxylate
  • Step 2 Synthesis of 5-cyclopropyl-N-(2-methylpiperidin-4-yl)-1,2-oxazole-3- carboxamide hydrochloride
  • a solution of tert-butyl 4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidine-1-carboxylate (1.55 g, 4.44 mmol) in DCM (50ml) was treated with 4M HCl in dioxane (15 ml) at rt for ⁇ 4h.
  • LCMS analysis showed complete reaction. The solvent was evaporated to dryness to yield 1.12 g (88%) of the amine as HCl salt as a white solid.
  • Step 3 Synthesis of benzyl 4-( ⁇ [4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidin-1-yl]sulfonyl ⁇ methyl)piperidine-1-carboxylate
  • Step 4 Synthesis of 5-cyclopropyl-N-[2-methyl-1-(piperidin-4- ylmethanesulfonyl) piperidin-4-yl]-1,2-oxazole-3-carboxamide
  • Step 5 Chiral separation of 5-cyclopropyl-N-[2-methyl-1-(piperidin-4- ylmethanesulfon l i eridin-4- l -1,2-oxazole-3-carboxamide
  • Step 1 Synthesis of benzyl 4-(((1S,3r,5R)-3-(5-cyclopropylisoxazole-3- carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate
  • Step 2 Synthesis of 5-cyclopropyl-N-((1R, 3rR, 5S)-8-(piperidin-4- ylmethylsulfonyl)-8-aza-bicyclo [3.2.1] octan-3-yl) isoxazole-3-carboxamide
  • Step 2 Synthesis of 5-cyclopropyl-N-[(2S,4S)-1-[1,4-dioxa-8- azaspiro[4.5]decane-8-sulfon l -2-meth l i eridin-4- l -1,2-oxazole-3-carboxamide O N O
  • Step 3 Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-oxopiperidin-1- ylsulfonyl)piperidin-4-yl isoxazole-3-carboxamide
  • Step 4 Synthesis of N-((2S,4S)-1-(4-aminopiperidin-1-ylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide trifluoroacetic acid
  • Step 1 Synthesis of N-((2S,4S)-1-(4-bromophenylsulfonyl)-2-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide
  • Step 2 Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-(prop-1-en-2- yl)phenylsulfonyl)piperidin-4- l isoxazole-3-carboxamide
  • the resulting solution was stirred at 90 o C overnight.
  • the reaction mixture was diluted with 10 mL of H 2 O andextracted with 3x50 mL of ethyl acetate.
  • Theorganic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:10-1:2).
  • Step 3 Synthesis of N-((2S,4S)-1-(4-(2-(2-chloroacetamido)propan-2- yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
  • the reaction mixture was diluted with of ice-water and the pH of the solution was adjusted to 7 with sodium carbonate (sat. aq.).
  • the resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate.
  • the residue was chromatographed on a silica gel column with dichloromethane/methanol (20:1). This resulted in 580 mg (99%) of N-((2S,4S)-1-(4-(2- (2-chloroacetamido)propan-2-yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide as a white solid.
  • Step 4 Synthesis of N-((2S,4S)-1-(4-(2-aminopropan-2-yl)phenylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
  • Step 1 Synthesis of (2S,4S)-4-(5-cyclopropylisoxazole-3-carboxamido)-2- methylpiperidine-1-sulfonyl chloride
  • Step 2 Synthesis of tert-butyl 8-((2S,4S)-4-(5-cyclopropylisoxazole-3- carboxamido)-2-methylpiperidin-1-ylsulfonyl)-3,8-diaza-bicyclo[3.2.1]octane-3- carboxylate
  • Step 3 Synthesis of 5-cyclopropyl-N-[(2S,4S)-1-[3,8-diazabicyclo[3.2.1]octane- 8-sulfonyl]-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide
  • Step 1 Synthesis of 5-cyclopropyl-N-((1R,3r,5S)-8-(4-oxocyclohexylsulfonyl)- 8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide

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Abstract

The present disclosure provides substituted piperidine compounds having Formula (I), and the pharmaceutically acceptable salts and solvates thereof, wherein R1, B, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2. Compounds of the present disclosure are especially useful for treating cancer.

Description

SUBSTITUTED PIPERIDINE COMPOUNDS BACKGROUND OF THE INVENTION Field of the Invention
[0001] The present disclosure provides substituted piperidines as SMYD protein inhibitors, such as SMYD3 and SMYD2 inhibitors, and therapeutic methods of treating conditions and diseases wherein inhibition of SMYD proteins such as SMYD3 and SMYD2 provides a benefit. Background
[0002] Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases. Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., SMYD proteins such as SMYD3 and SMYD2), many of which are associated with genetic alterations that can cause human disease, such as proliferative disorders. Thus, there is a need for the development of small molecules that are capable of inhibiting the activity of SMYD proteins such as SMYD3 and SMYD2. BRIEF SUMMARY OF THE INVENTION [0003] In one aspect, the present disclosure provides substituted piperidine compounds represented by any one of Formulae I-X below, and the pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as "Compounds of the Disclosure."
[0004] In another aspect, the present disclosure provides a Compound of the Disclosure and one or more pharmaceutically acceptable carriers.
[0005] In another aspect, the present disclosure provides a method of inhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a mammal, comprising administering to the mammal an effective amount of at least one Compound of the Disclosure.
[0006] In another aspect, the present disclosure provides methods for treating a disease, disorder, or condition, e.g., cancer, responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, comprising administering a therapeutically effective amount of a Compound of the Disclosure.
[0007] In another aspect, the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD3.
[0008] In another aspect, the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD2.
[0009] In another aspect, the present disclosure provides the use of Compounds of the Dicslosure as inhibitors of SMYD proteins.
[0010] In another aspect, the present disclosure provides a pharmaceutical composition for treating a disease, disorder, or condition responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Compound of the Disclosure in a mixture with one or more pharmaceutically acceptable carriers.
[0011] In another aspect, the present disclosure provides Compounds of the Disclosure for use in treating cancer in a mammal, e.g., breast, cervical, colon, kidney, liver, head and neck, skin, pancreatic, ovary, esophageal, lung, and prostate cancer.
[0012] In another aspect, the present disclosure provides a Compound of the Disclosure for use in the manufacture of a medicament for treating cancer in a mammal.
[0013] In another aspect, the present disclosure provides kit comprising a Compound of the Disclosure.
[0014] Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
[0015] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed. DETAILED DESCRIPTION OF THE INVENTION [0016] One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD proteins. In view of this property, the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD proteins.
[0017] One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD3. In view of this property, the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD3.
[0018] One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD2. In view of this property, the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD2.
[0019] In one embodiment, Compounds of the Disclosure are compounds having Formula I:
Figure imgf000004_0001
and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein:
[0020] B is:
Figure imgf000004_0002
;
[0021] X is selected from the group consisting of -S(=O)2-, -S(=O)2N(R7)-, -S(=O)2C(R8)(H)-, -C(=O)-, -C(=O)N(R7)-, -C(=O)O-, -C(=O)C(R8)(H)-, and -S(=O)2N(R7)C(=O)N(R11)-; or X is absent, (i.e., Z forms a bond with the nitrogen atom),
[0022] wherein the sulfur atom of -S(=O)2N(R7)-, -S(=O)2C(R8)(H)-, or -S(=O) 1
2N(R7)C(=O)N(R1 )- is attached to the nitrogen atom of B, the carbon atom of -C(=O)N(R7)- or -C(=O)O- is attached to the nitrogen atom of B, and the carbonyl carbon atom of -C(=O)C(R8)(H)- is attached the nitrogen atom of B; [0023] Z is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, [(cycloalkyl)alkylamino]alkyl, [(heterocyclo)alkylamino]alkyl, alkoxyalkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-12 cycloalkyl, aralkyl, and heteroaralkyl;
[0024] R1 is selected from the group consisting of ethyl, n-propyl, isopropyl, isobutyl, and cyclopropyl;
[0025] R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl; or
[0026] R2a and R2b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R3a, R3b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0027] R3a and R3b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0028] R4a and R4b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R3a, R3b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0029] R5a and R5b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R3a, R3b, R4a, and R4b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0030] R2a and R5a taken together form a C1-4 bridge; and R2b, R3a, R3b, R4a, R4b, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0031] R3a and R4a taken together form a C1-4 bridge; and R2a, R2b, R3b, R4a, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0032] R2a and R4a taken together form a C1-4 bridge; and R2b, R3a, R3b, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or [0033] R3a and R5a taken form a C1-4 bridge; and R2a, R2b, R3b, R4a, R4b, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl;
[0034] R6 is selected from the group consisting of hydrogen and C1-4 alkyl;
[0035] R7 is selected from the group consisting of hydrogen and C1-4 alkyl;
[0036] R8 is selected from the group consisting of hydrogen, C1-4 alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and -N(R9)C(=O)R10;
[0037] R9 is selected from the group consisting of hydrogen and C1-4 alkyl;
[0038] R10 is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, and (dialkylamino)alkyl; and
[0039] R11 is selected from the group consisting of hydrogen and C1-4 alkyl.
[0040] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is selected from the group consisting of ethyl and cyclopropyl.
[0041] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of optionally substituted C1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-12 cycloalkyl, aralkyl, and heteroaralkyl, when X is absent.
[0042] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
Figure imgf000006_0001
;
R6 is selected from the group consisting of hydrogen and C1-4 alkyl; and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, R6 is selected from the group consisting of hydrogen and methyl. In another embodiment, R6 is hydrogen. [0043] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
Figure imgf000007_0001
R2a is selected from the group consisting of halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl; and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, B is selected from the rou consistin of:
Figure imgf000007_0002
.
In another embodiment, R2a is selected from the group consisting of methyl, ethyl, phenyl, -CF3, -CO2Et, and -CH2OH. In another embodiment, R2a is -CH2Ph.
[0044] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
Figure imgf000007_0003
R3a is selected from the group consisting of halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl; and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, B is selected from the rou consistin of:
Figure imgf000007_0004
In another embodiment, R3a is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, and -CH2Ph. In another embodiment, R3a is -CH2Ph. [0045] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
Figure imgf000008_0001
R2a and R2b are each independently selected from the group consisting of halo and C1-6 alkyl; or R2a and R2b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, B is selected from the group consisting of:
Figure imgf000008_0004
and R2a and R2b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl. In another embodiment, B is selected from the group consisting of:
Figure imgf000008_0003
In another embodiment, B is selected from the group consisting of:
Figure imgf000008_0002
and R2a and R2b are each independently selected from the group consisting of halo and C1-4 alkyl. In another embodiment, R2a and R2b are selected from the group consisting of fluoro and methyl. [0046] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
Figure imgf000009_0001
R3a and R3b are each independently selected from the group consisting of halo and C1-6 alkyl; or
R3a and R3b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, B is selected from the group consisting of:
Figure imgf000009_0004
and R3a and R3b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl. In another embodiment, B is selected from the group consisting of:
,
.
.
Figure imgf000009_0002
In another embodiment, B is selected from the group consisting of:
Figure imgf000009_0003
and R3a and R3b are each independently selected from the group consisting of halo and C1-4 alkyl. In another embodiment, R3a and R3b are selected from the group consisting of fluoro and methyl. [0047] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
Figure imgf000010_0001
R3a and R5a are each independently C1-6 alkyl; or R3a and R5a taken together form a C1-4 bridge; and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, B is selected from the group consisting of:
Figure imgf000010_0004
In another embodiment, R3a and R5a are each independently C1-4 alkyl. In another embodiment, R3a and R5a are each methyl or ethyl.
[0048] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
Figure imgf000010_0002
and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, B is selected from the group consisting of:
Figure imgf000010_0003
.
[0049] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
Figure imgf000011_0001
R2a and R3a are each independently C1-6 alkyl; and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, B is:
.
Figure imgf000011_0002
In another embodiment, R2a and R3a are each independently C1-4 alkyl. In another embodiment, R2a and R3a are each methyl or ethyl.
[0050] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
Figure imgf000011_0003
R3a and R4a are each independently C1-6 alkyl; or R3a and R4a taken together form a C1-4 bridge; and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, B is:
.
Figure imgf000011_0004
In another embodiment, R3a and R4a are each independently C1-4 alkyl. In another embodiment, R3a and R4a are each methyl or ethyl. [0051] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is selected from the group consisting of:
Figure imgf000012_0001
and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, B is selected from the rou consistin of:
Figure imgf000012_0002
.
In another embodiment, B is selected from the rou consistin of:
Figure imgf000012_0003
[0052] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
Figure imgf000012_0004
R2a and R5a are each independently selected from the group consisting of C1-6 alkyl and alkoxycarbonyl; or R2a and R5a taken together form a C1-4 bridge; and R1, X, and Z are as defined above in connection with Formula I. In another embodiment, B is:
Figure imgf000012_0005
.
Figure imgf000013_0001
In another embodiment, R2a and R5a are each independently selected from the group consisting of C1-4 alkyl and alkoxycarbonyl. In another embodiment, R2a and R5a are each independently selected from the group consisting of methyl and -CO2Me.
[0053] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is -S(=O)2- and R1, B, and Z are as defined above in connection with Formula I.
[0054] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is -C(=O)- and R1, B, and Z are as defined above in connection with Formula I.
[0055] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is absent and R1, B, and Z are as defined above in connection with Formula I.
[0056] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is -S(=O)2N(H)- and R1, B, and Z are as defined above in connection with Formula I.
[0057] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is -C(=O)N(H)- and R1, B, and Z are as defined above in connection with Formula I.
[0058] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is -C(=O)O- and R1, B, and Z are as defined above in connection with Formula I.
[0059] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is -S(=O)2CH2- and R1, B, and Z are as defined above in connection with Formula I.
[0060] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is -C(=O)CH2- and R1, B, and Z are as defined above in connection with Formula I.
[0061] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is selected from the group consisting of:
Figure imgf000014_0001
;
R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and -N(R9)C(=O)R10; and R1, R9, R10, B, and Z are as defined above in connection with Formula I. In another embodiment, R8 is selected from the group consisting of -NH2, -CH2NH2, and -N(H)C(=O)R10.
[0062] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is selected from the group consisting of:
Figure imgf000014_0002
R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and -N(R9)C(=O)R10; and R1, R9, R10, B, and Z are as defined above in connection with Formula I. In another embodiment, R8 is selected from the group consisting of -NH2, -CH2NH2, and -N(H)C(=O)R10.
[0063] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (aralkylamino)alkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and optionally substituted C3-12 cycloalkyl.
[0064] In another embodiment, Compounds of the Disclosure are compounds having Formula II:
Figure imgf000015_0001
and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein
[0065] R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl; or
[0066] R2a and R2b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R3a, R3b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0067] R3a and R3b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0068] R4a and R4b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R3a, R3b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0069] R5a and R5b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R3a, R3b, R4a, and R4b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0070] R2a and R5a taken together form a C1-4 bridge; and R2b, R3a, R3b, R4a, R4b, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0071] R3a and R4a taken together form a C1-4 bridge; and R2a, R2b, R3b, R4a, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0072] R2a and R4a taken together form a C 2b
1-4 bridge; and R , R3a, R3b, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or [0073] R3a and R5a taken form a C1-4 bridge; and R2a, R2b, R3b, R4a, R4b, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl;
[0074] R6 is selected from the group consisting of hydrogen and C1-4 alkyl;
[0075] with the proviso that a) one or more of R2a, R3a, R4a, and R5a is independently selected from the group consisting of halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl; or b) R6 is C1-4 alkyl; and
[0076] R1, X, and Z are as defined in connection with Formula I.
[0077] In another embodiment, Compounds of the Disclosure are compounds having Formula II, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of optionally substituted C1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-12 cycloalkyl, aralkyl, and heteroaralkyl, when X is absent.
[0078] In another embodiment, Compounds of the Disclosure are compounds having Formula II, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein
[0079] R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl; or
[0080] R2a and R2b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R3a, R3b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0081] R3a and R3b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or
[0082] R4a and R4b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R3a, R3b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or [0083] R5a and R5b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R3a, R3b, R4a, and R4b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; and
[0084] R1, R6, X, and Z are as defined in connection with Formula I.
[0085] In another embodiment, Compounds of the Disclosure are compounds having Formula III:
Figure imgf000017_0001
and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z and R1 are as defined above in connection with Formula I. In another embodiment, Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C6-14 aryl, and optionally substituted 4- to 14-membered heterocyclo.
[0086] In another embodiment, Compounds of the Disclosure are compounds having Formula IV:
Figure imgf000017_0002
and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z and R1 are as defined above in connection with Formula I. In another embodiment, Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C6-14 aryl, and optionally substituted 4- to 14-membered heterocyclo.
[0087] In another embodiment, Compounds of the Disclosure are compounds having Formula V:
Figure imgf000017_0003
and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z and R1 are as defined above in connection with Formula I. In another embodiment, Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C3-12 cycloalkyl. It will be understood by those of ordinary skill in the art that compounds having Formula V can be drawn in various ways, e.g.,
Figure imgf000018_0001
.
[0088] In another embodiment, Compounds of the Disclosure are compounds having Formula VI:
Figure imgf000018_0002
and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z and R1 are as defined above in connection with Formula I. In another embodiment, Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C3-12 cycloalkyl. It will be understood by those of ordinary skill in the art that compounds having Formula VI can be drawn in various ways, e.g.,
Figure imgf000019_0001
.
[0089] In another embodiment, Compounds of the Disclosure are compounds having Formula VII:
Figure imgf000019_0002
and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z and R1 are as defined above in connection with Formula I. In another embodiment, Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C3-12 cycloalkyl.
[0090] In another embodiment, Compounds of the Disclosure are compounds having Formula VIII:
Figure imgf000019_0003
and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z and R1 are as defined above in connection with Formula I. In another embodiment, Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C3-12 cycloalkyl.
[0091] In another embodiment, Compounds of the Disclosure are compounds having Formula IX:
Figure imgf000020_0001
and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z and R1 are as defined above in connection with Formula I.
[0092] In another embodiment, Compounds of the Disclosure are compounds having Formula X:
Figure imgf000020_0002
and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z and R1 are as defined above in connection with Formula I.
[0093] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is ethyl.
[0094] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is ethyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
[0095] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is n-propyl.
[0096] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is n-propyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl. [0097] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is isopropyl.
[0098] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is isopropyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
[0099] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is isobutyl.
[0100] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is isobutyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
[0101] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is cyclopropyl.
[0102] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is cyclopropyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
[0103] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is (heterocyclo)alkyl.
[0104] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is a (heterocyclo)alkyl having the following structure:
Figure imgf000022_0001
;
wherein R12 is selected from the group consisting of hydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. In another embodiment, R12 is selected from the group consisting of hydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl.
[0105] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of:
Figure imgf000022_0002
.
[0106] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R1 is cyclopropyl and Z is selected from the group consisting of:
Figure imgf000022_0003
.
[0107] In another embodiment, Compounds of the Disclosure are compounds of Table 1, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof. The chemical names of the compounds of Table 1 are provided in Table 1A.
[0108] In another embodiment, Compounds of the Disclosure are compounds of Table 2, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof. The chemical names of the compounds of Table 2 are provided in Table 2A.
[0109] In another embodiment, Compounds of the Disclosure are compounds of Table 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof. The chemical names of the compounds of Table 3 are provided in Table 3A.
[0110] In another embodiment, Compounds of the Disclosure are compounds of Tables 1 and 2, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
[0111] In another embodiment, Compounds of the Disclosure are compounds of Tables 1, 2, and 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
[0112] In another embodiment, Compounds of the Disclosure are compounds of Tables 1, 1A, 2, 2A, 3, and 3A, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
[0113] In another embodiment, Compounds of the Disclosure are selected from the group consisting of:
[0114] N-((1R,3R,5S)-8-(((1r,4R)-4-aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide;
[0115] N-((2S,4S)-1-((4-aminopiperidin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide;
[0116] N-((2S,4S)-1-((4-(2-aminopropan-2-yl)phenyl)sulfonyl)-2-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide;
[0117] N-((1R,3r,5S)-8-((4-aminopiperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)-5-cyclopropylisoxazole-3-carboxamide;
[0118] 5-cyclopropyl-N-((1R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide; and
[0119] N-((1R,3r,5S)-8-((4-(2-aminopropan-2-yl)phenyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide,
[0120] and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof. [0121] In another embodiment, Compounds of the Disclosure are selected from the group consisting of:
[0122] N-((1R,3R,5S)-8-(((1r,4R)-4-aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide;
[0123] N-((2S,4S)-1-((4-aminopiperidin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide;
[0124] N-((2S,4S)-1-((4-(2-aminopropan-2-yl)phenyl)sulfonyl)-2-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide;
[0125] N-((1R,3r,5S)-8-((4-aminopiperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)-5-cyclopropylisoxazole-3-carboxamide; and
[0126] 5-cyclopropyl-N-((1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide,
[0127] and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof.
[0128] It should be appreciated that the Compounds of the Disclosure in certain embodiments are the free base, various salts, and hydrate forms, and are not limited to the particular salt listed in Table 1, Table 2, or Table 3.
Figure imgf000025_0001
- 24 -
Figure imgf000026_0001
- 25 -
Figure imgf000027_0001
- 26 -
Figure imgf000028_0001
- 27 -
Figure imgf000029_0001
- 28 -
Figure imgf000030_0001
- 29 -
Figure imgf000031_0001
- 30 -
Figure imgf000032_0001
- 31 -
Figure imgf000033_0001
- 32 -
Figure imgf000034_0001
- 33 -
Figure imgf000035_0001
- 34 -
Figure imgf000036_0001
- 35 -
Figure imgf000037_0001
- 36 -
Figure imgf000038_0001
- 37 -
Figure imgf000039_0001
- 38 -
Figure imgf000040_0001
- 39 -
Figure imgf000041_0001
- 40 -
Figure imgf000042_0001
- 41 -
Figure imgf000043_0001
- 42 -
Figure imgf000044_0001
- 43 -
Figure imgf000045_0001
- 44 -
Figure imgf000046_0001
- 45 -
Figure imgf000047_0001
- 46 -
Figure imgf000048_0001
- 47 -
Figure imgf000049_0001
- 48 -
Figure imgf000050_0001
- 49 -
Figure imgf000051_0001
- 50 -
Figure imgf000052_0001
- 51 -
Figure imgf000053_0001
- 52 -
Figure imgf000054_0001
- 53 -
Figure imgf000055_0001
- 54 -
Figure imgf000056_0001
- 55 -
Figure imgf000057_0001
- 56 -
Figure imgf000058_0001
- 57 -
Figure imgf000059_0001
- 58 -
Figure imgf000060_0001
- 59 -
Figure imgf000061_0001
- 60 -
Figure imgf000062_0001
- 61 -
Figure imgf000063_0001
- 62 -
Figure imgf000064_0001
- 63 -
Figure imgf000065_0001
- 64 -
Figure imgf000066_0001
- 65 -
Figure imgf000067_0001
- 66 -
Figure imgf000068_0001
- 67 -
Figure imgf000069_0001
- 68 -
Figure imgf000070_0001
- 69 -
Figure imgf000071_0001
- 70 -
Figure imgf000072_0001
- 71 -
Figure imgf000073_0001
- 72 -
Figure imgf000074_0001
- 73 -
Figure imgf000075_0001
- 74 -
Figure imgf000076_0001
- 75 -
Figure imgf000077_0001
- 76 -
Figure imgf000078_0001
- 77 -
Figure imgf000079_0001
- 78 -
- 79 -
Figure imgf000081_0001
- 80 -
Figure imgf000082_0001
- 81 -
Figure imgf000083_0001
- 82 -
Figure imgf000084_0001
- 83 -
Figure imgf000085_0001
- 84 -
Figure imgf000086_0001
- 85 -
Figure imgf000087_0001
- 86 -
Figure imgf000088_0001
- 87 -
Table 2
Figure imgf000089_0001
- 88 -
Figure imgf000090_0001
- 89 -
Figure imgf000091_0001
540 None 660 HCl
- 90 -
Figure imgf000092_0001
- 91 -
Figure imgf000093_0001
- 92 -
Figure imgf000094_0001
- 93 -
Figure imgf000095_0001
- 94 -
Figure imgf000096_0001
- 95 -
Figure imgf000097_0001
- 96 -
Figure imgf000098_0001
- 97 -
Figure imgf000099_0001
- 98 -
Figure imgf000100_0001
- 99 -
Figure imgf000101_0001
- 100 -
Figure imgf000102_0001
- 101 -
Figure imgf000103_0001
- 102 -
Figure imgf000104_0001
- 103 -
Figure imgf000105_0001
- 104 -
Figure imgf000106_0001
- 105 -
Figure imgf000107_0001
- 106 -
Figure imgf000108_0001
- 107 -
Figure imgf000109_0001
- 108 -
Figure imgf000110_0001
- 109 -
Figure imgf000111_0001
- 110 -
Figure imgf000112_0001
- 111 -
Figure imgf000113_0001
- 112 -
Figure imgf000114_0001
- 113 -
Figure imgf000115_0001
- 114 -
Figure imgf000116_0001
- 115 -
Table 3
Figure imgf000117_0001
- 116 -
Figure imgf000118_0001
- 117 -
Figure imgf000119_0001
- 118 -
Figure imgf000120_0001
- 119 -
Figure imgf000121_0001
- 120 -
Figure imgf000122_0001
- 121 -
Figure imgf000123_0001
- 122 -
Figure imgf000124_0001
- 123 -
Figure imgf000125_0001
- 124 -
Figure imgf000126_0001
- 125 -
Figure imgf000127_0001
- 126 -
Figure imgf000128_0001
- 127 -
Figure imgf000129_0001
- 128 -
Figure imgf000130_0001
- 129 -
Figure imgf000131_0001
- 130 -
Figure imgf000132_0001
- 131 -
Figure imgf000133_0001
- 132 -
Figure imgf000134_0001
- 133 -
Figure imgf000135_0001
- 134 -
Figure imgf000136_0001
- 135 -
Figure imgf000137_0001
- 136 -
Figure imgf000138_0001
- 137 -
Figure imgf000139_0001
- 138 -
Figure imgf000140_0001
- 139 - Table 1A
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0002
Table 2A
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0002
Table 3A
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0002
[0129] In another embodiment, a Compound of the Disclosure is a compound having Formulae I-X, provided that the compound is not:
Figure imgf000217_0001
Figure imgf000218_0001
N-(1-((4- acetamidophenyl)sulfonyl)piperidin- 4-yl)-5-cyclopropylisoxazole-3- carboxamide 5-cyclopropyl-N-(1-(4-isopropyl-5- (pyridin-4-yl)pyrimidin-2- yl)piperidin-4-yl)isoxazole-3- carboxamide O N N-(1-(7,8-dihydro-5H-pyrano[4,3- O N N d]pyrimidin-2-yl)piperidin-4-yl)-5- N O
N ethylisoxazole-3-carboxamide H 5-ethyl-N-(1-(4-isopropyl-5- (pyridin-4-yl)pyrimidin-2- yl)piperidin-4-yl)isoxazole-3- carboxamide
Figure imgf000219_0001
[0130] In some embodiments, the disclosure relates to pharmaceutical compositions comprising one or more of the following compounds:
Structure Name
O HN N O
N 5-cyclopropyl-N-(piperidin-4- H yl)isoxazole-3-carboxamide
N-(8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide O
H2 N N N
O N-(1 -(2-amino-2-oxoethyl)piperidin-4- N O H yl)-5-cyclopropylisoxazole-3- carboxamide
Figure imgf000219_0002
Figure imgf000220_0001
N N
O 5-cyclopropyl-N-(1 -(2,6- N N
O dimethylpyrimidin-4-yl)piperidin-4- N
H yl)isoxazole-3-carboxamide N-(1-((4- acetamidophenyl)sulfonyl)piperidin-4- yl)-5-cyclopropylisoxazole-3- carboxamide
5-cyclopropyl-N-(1-(4-isopropyl-5- (pyridin-4-yl)pyrimidin-2-yl)piperidin-4- yl)isoxazole-3-carboxamide
O N N-(1-(7,8-dihydro-5H-pyrano[4,3- O N N d]pyrimidin-2-yl)piperidin-4-yl)-5- N O
N ethylisoxazole-3-carboxamide H 5-ethyl-N-(1-(4-isopropyl-5-(pyridin-4- yl)pyrimidin-2-yl)piperidin-4- yl)isoxazole-3-carboxamide
Figure imgf000221_0001
and a pharmeceutically acceptable carier.
[0131] In some embodiments, the disclosure relates to a method of inhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a subject, comprising administering to a subject in need thereof an effective amount of at least one of the following compounds:
Figure imgf000221_0002
Figure imgf000222_0001
Figure imgf000223_0001
Definitions
[0132] For the purpose of the present disclosure, the term "alkyl" as used by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C1-12 alkyl) or the number of carbon atoms designated (i.e., a C1 alkyl such as methyl, a C2 alkyl such as ethyl, a C3 alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is chosen from a straight chain C1-10 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C3-10 alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C1-6 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C3-6 alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C1-4 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C3-4 alkyl group. In another embodiment, the alkyl group is chosen from a straight or branched chain C3-4 alkyl group. In another embodiment, the alkyl group is partially or completely deuterated, i.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms. Non-limiting exemplary C1-10 alkyl groups include methyl (including -CD3), ethyl, propyl, isopropyl, butyl, sec-butyl, tert- butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting exemplary C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl. Non-limiting exemplary C1-4 groups include methyl, ethyl, propyl, isopropyl, and tert-butyl.
[0133] For the purpose of the present disclosure, the term "optionally substituted alkyl" as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, alkoxycarbonyl, and carboxyalkyl. In one embodiment, the alkyl is a C1-4 alkyl. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. Non-limiting exemplary optionally substituted alkyl groups include -CH2CH2NO2, -CH2CH2CO2H, -CH2CH2SO2CH3, -CH2CH2COPh, and -CH2C6H11.
[0134] For the purpose of the present disclosure, the term "cycloalkyl" as used by itself or as part of another group refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl) or the number of carbons designated. In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is chosen from a C3-8 cycloalkyl group. In another embodiment, the cycloalkyl group is chosen from a C3-6 cycloalkyl group. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.
[0135] For the purpose of the present disclosure, the term "optionally substituted cycloalkyl" as used by itself or as part of another group means that the cycloalkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkylamino, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. In one embodiment, the optionally substituted cycloalkyl is substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In one embodiment, the optionally substituted cycloalkyl is substituted with at least one amino, alkylamino, or dialkylamino group. The term "amino-substituted cycloalkyl" as used by itself or as part of another group means that the optionally susbstituted cycloalkyl as defined above is substituted with at least one amino group. In one embodiment, the amino-substituted cycloalkyl is an amino-substituted cyclohexyl group. Non-limiting exemplary optionally substituted cycloalkyl groups include:
Figure imgf000226_0001
Figure imgf000226_0002
.
[0136] For the purpose of the present disclosure, the term "cycloalkenyl" as used by itself or part of another group refers to a partially unsaturated cycloalkyl group as defined above. In one embodiment, the cycloalkenyl has one carbon-to-carbon double bond. In another embodiment, the cycloalkenyl group is chosen from a C4-8 cycloalkenyl group. Exemplary cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
[0137] For the purpose of the present disclosure, the term "optionally substituted cycloalkenyl" as used by itself or as part of another group means that the cycloalkenyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, the optionally substituted cycloalkenyl is substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, the optionally substituted cycloalkenyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkenyl is substituted with one substituent. In another embodiment, the cycloalkenyl is unsubstituted.
[0138] For the purpose of the present disclosure, the term "alkenyl" as used by itself or as part of another group refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is chosen from a C2-6 alkenyl group. In another embodiment, the alkenyl group is chosen from a C2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
[0139] For the purpose of the present disclosure, the term "optionally substituted alkenyl" as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo.
[0140] For the purpose of the present disclosure, the term "alkynyl" as used by itself or as part of another group refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-to-carbon triple bond. In one embodiment, the alkynyl group is chosen from a C2-6 alkynyl group. In another embodiment, the alkynyl group is chosen from a C2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
[0141] For the purpose of the present disclosure, the term "optionally substituted alkynyl" as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.
[0142] For the purpose of the present disclosure, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms. In another embodiment, the haloalkyl group is chosen from a C1-4 haloalkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.
[0143] For the purpose of the present disclosure, the term "fluoroalkyl" as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine atoms. In one embodiment, the alkyl group is substituted by one, two, or three fluorine atoms. In another embodiment, the fluoroalkyl group is chosen from a C1-4 fluoroalkyl group. Non-limiting exemplary fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl.
[0144] For the purpose of the present disclosure, the term "hydroxyalkyl" as used by itself or as part of another group refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups. In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. In another embodiment, the hydroxyalkyl group is chosen from a C1-4 hydroxyalkyl group. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2- yl.
[0145] For the purpose of the present disclosure, the term "alkoxy" as used by itself or as part of another group refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom. In one embodiment, the alkoxy group is chosen from a C1-4 alkoxy group. In another embodiment, the alkoxy group is chosen from a C1-4 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, and tert-butoxy.
[0146] For the purpose of the present disclosure, the term "alkylthio" as used by itself or as part of another group refers to a sulfur atom substituted by an optionally substituted alkyl group. In one embodiment, the alkylthio group is chosen from a C1-4 alkylthio group. Non-limiting exemplary alkylthio groups include -SCH3, and -SCH2CH3.
[0147] For the purpose of the present disclosure, the term "alkoxyalkyl" as used by itself or as part of another group refers to an alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.
[0148] For the purpose of the present disclosure, the term "haloalkoxy" as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
[0149] For the purpose of the present disclosure, the term "heteroalkyl" as used by itself or part of another group refers to a stable straight or branched chain hydrocarbon radical containing 1 to 10 carbon atoms and at least two heteroatoms, which can be the same or different, selected from O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) can optionally be oxidized; and/or 2) the nitrogen atom(s) can optionally be quaternized. The heteroatoms can be placed at any interior position of the heteroalkyl group or at a position at which the heteroalkyl group is attached to the remainder of the molecule. In one embodiment, the heteroalkyl group contains two oxygen atoms. In one embodiment, the heteroalkyl contains one oxygen and one nitrogen atom. In one embodiment, the heteroalkyl contains two nitrogen atoms. Non-limiting exemplary heteroalkyl groups include -CH2OCH2CH2OCH3, -OCH2CH2OCH2CH2OCH3, -CH2NHCH2CH2OCH2, -OCH2CH2NH2, -NHCH2CH2N(H)CH3, -CH2CH2CH2N(H)CH2CH2NH2, -CH2CH2CH2N(H)CH2CH2N(H)CH3, -NHCH2CH2OCH3, -N(CH3)CH2CH2CH2OCH3, and -OCH2CH2OCH3.
[0150] For the purpose of the present disclosure, the term "aryl" as used by itself or as part of another group refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms (i.e., C6-14 aryl). Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is chosen from phenyl or naphthyl. In one embodiment, the aryl group is phenyl.
[0151] For the purpose of the present disclosure, the term "optionally substituted aryl" as used herein by itself or as part of another group means that the aryl as defined above is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C1-4 haloalkoxy)alkyl, (heteroaryl)alkyl, -N(R43)(R44), and -N(H)C(=O)-R45, wherein R43 is hydrogen or C1-4 alkyl; R44 is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R45 is alkyl, optionally substituted aryl or optionally substituted heteroaryl. In one embodiment, the optionally substituted aryl is substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C1-4 haloalkoxy)alkyl, (heteroaryl)alkyl, -N(R43)(R44), and -N(H)C(=O)-R45. In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. In another embodiment, the optionally substituted phenyl has at least one amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl substituent. The term "(amino)alkyl-substituted phenyl" as used by itself or as part of another group means that the optionally susbstituted phenyl as defined above is substituted with at least one (amino)alkyl group. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di- methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, 2-phenylpropan-2- amine,
Figure imgf000231_0001
.
The term optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include:
Figure imgf000231_0002
. [0152] For the purpose of the present disclosure, the term "aryloxy" as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.
[0153] For the purpose of the present disclosure, the term "heteroaryloxy" as used by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom.
[0154] For the purpose of the present disclosure, the term "aralkyloxy" or "arylalkyloxy" as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH2O-.
[0155] For the purpose of the present disclosure, the term "heteroaryl" or "heteroaromatic" refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms (i.e., a 5- to 14-membered heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen or sulfur. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, ȕ-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H- imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2- yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3- yl, isoxazol-4-yl, and isoxazol-5-yl). The term "heteroaryl" is also meant to include possible N-oxides. Exemplary N-oxides include pyridyl N-oxide.
[0156] For the purpose of the present disclosure, the term "optionally substituted heteroaryl" as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R43)(R44), or -N(H)C(=O)-R45, wherein R43 is hydrogen or C1-4 alkyl; R44 is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R45 is alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In another embodiment, the optionally substituted heteroaryl is substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R43)(R44), or -N(H)C(=O)-R45. In one embodiment, the optionally substituted heteroaryl has one substituent. In one embodiment, the substituent is amino, alkylamino, dialkylamino, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, -N(R43)(R44), or -N(H)C(=O)-R45. In one embodiment, the optionally substituted is an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can be substituted. [0157] For the purpose of the present disclosure, the term "heterocycle" or "heterocyclo" as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members (i.e., a 3- to 14-membered heterocyclo) and at least one heteroatom. Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be quaternized. The term "heterocyclo" is meant to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as ȕ-lactam, Ȗ-lactam, į- lactam and İ-lactam, and cyclic carbamate groups such as oxazolidinyl-2-one. The term "heterocyclo" is also meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl, indolinyl-2-one, benzo[d]oxazolyl-2(3H)-one. In one embodiment, the heterocyclo group is chosen from a 4-, 5-, 6-, 7- or 8-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 8-, 9-, 10-, 11-, or 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, 8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6-azaspiro[3.4]octane, indolinyl, indolinyl-2-one, 1,3-dihydro-2H-benzo[d]imidazol-2- one.
[0158] For the purpose of the present disclosure, the term "optionally substituted heterocyclo" as used herein by itself or part of another group means the heterocyclo as defined above is either unsubstituted or substituted with one to four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkylamino, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. Substitution may occur on any available carbon or nitrogen atom, and may form a spirocycle. In another embodiment, the optionally substituted heterocyclo is substituted with one to four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, the optionally substituted heterocyclo is substituted with at least one amino, alkylamino, or dialkylamino group. The term "amino-substituted heterocyclo" as used by itself or as part of another group means that the optionally susbstituted heterocyclo as defined above is substituted with at least one amino group. Likewise, the term "alkylamino-substituted heterocyclo" as used by itself or as part of another group means that the optionally susbstituted heterocyclo as defined above is substituted with at least one alkylamino group. In one embodiment, the amino-substituted or alkylamino- substituted heterocyclo is an amino-substituted or alkylamino-substituted piperidine. Non-limiting exemplary optionally substituted heterocyclo groups include:
Figure imgf000235_0001
Figure imgf000236_0001
.
[0159] For the purpose of the present disclosure, the term "amino" as used by itself or as part of another group refers to -NH2.
[0160] For the purpose of the present disclosure, the term "alkylamino" as used by itself or as part of another group refers to -NHR22, wherein R22 is C1-6 alkyl. In one embodiment, R22 is C1-4 alkyl. Non-limiting exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.
[0161] For the purpose of the present disclosure, the term "dialkylamino" as used by itself or as part of another group refers to -NR23aR23b, wherein R23a and R23b are each independently C1-6 alkyl. In one embodiment, R23a and R23b are each independently C1-4 alkyl. Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.
[0162] For the purpose of the present disclosure, the term "hydroxyalkylamino" as used by itself or as part of another group refers to -NHR24, wherein R24 is hydroxyalkyl.
[0163] For the purpose of the present disclosure, the term "cycloalkylamino" as used by itself or as part of another group refers to -NR25aR25b, wherein R25a is optionally substituted cycloalkyl and R25b is hydrogen or C1-4 alkyl.
[0164] For the purpose of the present disclosure, the term "aralkylamino" as used by itself or as part of another group refers to -NR26aR26b, wherein R26a is aralkyl and R26b is hydrogen or C1-4 alkyl. Non-limiting exemplary aralkylamino groups include -N(H)CH2Ph, -N(H)CHPh2, and -N(CH3)CH2Ph.
[0165] For the purpose of the present disclosure, the term "(cycloalkyl)alkylamino" as used by itself or as part of another group refers to -NR26cR26d, wherein R26c is (cycloalkyl)alkyl and R26d is hydrogen or C1-4 alkyl. Non-limiting exemplary (cycloalkyl)alkylamino groups include:
Figure imgf000237_0001
.
[0166] For the purpose of the present disclosure, the term "(heterocyclo)alkylamino" as used by itself or as part of another group refers to -NR26eR26f, wherein R26e is (heterocyclo)alkyl and R26f is hydrogen or C1-4 alkyl. Non-limiting exemplary (heterocyclo)alky
Figure imgf000237_0002
.
[0167] For the purpose of the present disclosure, the term "(amino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with an amino group. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (amino)alkyl groups include -CH2NH2, -C(CH3)NH2, -C(NH2)(H)CH3, -CH2CH2NH2, -CH2C(NH2)(H)CH3, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and -CH2C(CH3)2CH2NH2.
[0168] For the purpose of the present disclosure, the term "(alkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with an alkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. A non-limiting exemplary (alkylamino)alkyl group is -CH2CH2N(H)CH3.
[0169] For the purpose of the present disclosure, the term "(dialkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted by a dialkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (dialkylamino)alkyl groups are -CH2CH2N(CH3)2.
[0170] For the purpose of the present disclosure, the term "(cycloalkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted by a cycloalkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (cycloalkylamino)alkyl groups include -CH2N(H)cyclopropyl, -CH2N(H)cyclobutyl, and -CH2N(H)cyclohexyl.
[0171] For the purpose of the present disclosure, the term "[(cycloalkyl)alkylamino]alkyl" as used by itself or as part of another group refers to an alkyl group substituted by a (cycloalkyl)alkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary ([(cycloalkyl)alkylamino]alkyl groups include:
Figure imgf000238_0001
[0172] For the purpose of the present disclosure, the term "[(heterocyclo)alkylamino]alkyl" as used by itself or as part of another group refers to an alkyl group substituted by a (heterocyclo)alkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary ([(heterocyclo)alkylamino]alkyl groups include:
Figure imgf000238_0002
.
[0173] For the purpose of the present disclosure, the term "(aralkylamino)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with an aralkylamino group. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (aralkylamino)alkyl groups include -CH2CH2CH2N(H)CH2Ph and -CH2CH2CH2N(H)CH2(4-CF3-Ph).
[0174] For the purpose of the present disclosure, the term "(cyano)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one or more cyano, e.g., -CN, groups. In one embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (cyano)alkyl groups include -CH2CH2CN, -CH2CH2CH2CN, and -CH2CH2CH2CH2CN.
[0175] For the purpose of the present disclosure, the term "(amino)(hydroxy)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one hydroxy group. In one embodiment, the alkyl is a C1-6 alkyl. In another embodiment, the alkyl is a C1-4 alkyl. Non-limiting exemplary (amino)(hydroxy)alkyl groups include:
Figure imgf000238_0003
. [0176] For the purpose of the present disclosure, the term "(amino)(aryl)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one optionally substituted aryl group. In one embodiment, the alkyl is a C1-6 alkyl. In one embodiment, the optionally substituted aryl group is an optionally substituted phenyl. Non-limiting exemplary (amino)(aryl)alkyl groups incl
Figure imgf000239_0001
.
[0177] For the purpose of the present disclosure, the term "(cycloalkyl)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one optionally substituted cycloalkyl group. In one embodiment, the alkyl is a C1-4 alkyl. In one embodiment, the cycloalkyl is a C3-6 cycloalkyl. In one embodiment, the optionally substituted cycloalkyl group is substituted with an amino or (amino)alkyl group. Non-limiting exemplary (cycloalkyl)alkyl groups include:
Figure imgf000239_0002
.
[0178] For the purpose of the present disclosure, the term "(hydroxy)(aryl)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one hydroxy group and one optionally substituted aryl group. In one embodiment, the alkyl is a C1-6 alkyl. In one embodiment, the optionally substituted aryl group is an optionally substituted phenyl. Non-limiting exemplary (hydroxy)(aryl)alkyl groups include:
Figure imgf000240_0001
.
[0179] For the purpose of the present disclosure, the term "carboxamido" as used by itself or as part of another group refers to a radical of formula -C(=O)NR26aR26b, wherein R26a and R26b are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or R26a and R26b taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. In one embodiment, R26a and R26b are each independently hydrogen or optionally substituted alkyl. Non-limiting exemplary carboxamido groups include -CONH2, -CON(H)CH3, CON(CH3)2, and -CON(H)Ph.
[0180] For the purpose of the present disclosure, the term "(carboxamido)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with a carboxamido group. Non-limiting exemplary (carboxamido)alkyl groups include -CH2CONH2, -C(H)CH3-CONH2, and -CH2CON(H)CH3.
[0181] For the purpose of the present disclosure, the term "sulfonamido" as used by itself or as part of another group refers to a radical of the formula -SO2NR27aR27b, wherein R27a and R27b are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R27a and R27b taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group. Non-limiting exemplary sulfonamido groups include -SO2NH2, -SO2N(H)CH3, and -SO2N(H)Ph.
[0182] For the purpose of the present disclosure, the term "alkylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted by an alkyl group. A non-limiting exemplary alkylcarbonyl group is -COCH3.
[0183] For the purpose of the present disclosure, the term "arylcarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted by an optionally substituted aryl group. A non-limiting exemplary arylcarbonyl group is -COPh.
[0184] For the purpose of the present disclosure, the term "alkylsulfonyl" as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO2-, substituted by any of the above-mentioned optionally substituted alkyl groups. A non-limiting exemplary alkylsulfonyl group is -SO2CH3.
[0185] For the purpose of the present disclosure, the term "arylsulfonyl" as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO2-, substituted by any of the above-mentioned optionally substituted aryl groups. A non-limiting exemplary arylsulfonyl group is -SO2Ph.
[0186] For the purpose of the present disclosure, the term "mercaptoalkyl" as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a–SH group.
[0187] For the purpose of the present disclosure, the term "carboxy" as used by itself or as part of another group refers to a radical of the formula -COOH.
[0188] For the purpose of the present disclosure, the term "carboxyalkyl" as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a -COOH. A non-limiting exemplary carboxyalkyl group is -CH2CO2H.
[0189] For the purpose of the present disclosure, the term "alkoxycarbonyl" as used by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted by an alkoxy group. In one embodiment, the alkoxy group is a C1-4 alkoxy. Non-limiting exemplary alkoxycarbonyl groups are -CO2Me and -CO2Et.
[0190] For the purpose of the present disclosure, the term "aralkyl" or "arylalkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the aralkyl group is a C1-4 alkyl substituted with one optionally substituted aryl group. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh2, -CH2(4-OH-Ph), and -CH(4-F-Ph)2.
[0191] For the purpose of the present disclosure, the term "ureido" as used by itself or as part of another group refers to a radical of the formula -NR30a-C(=O)-NR30bR30c, wherein R30a is hydrogen, alkyl, or optionally substituted aryl, and R30b and R30c are each independently hydrogen, alkyl, or optionally substituted aryl, or R30b and R30c taken together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclo group. Non-limiting exemplary ureido groups include -NH-C(C=O)-NH2 and -NH-C(C=O)-NHCH3.
[0192] For the purpose of the present disclosure, the term "guanidino" as used by itself or as part of another group refers to a radical of the formula -NR28a-C(=NR29)-NR28bR28c, wherein R28a, R28b, and R28c are each independently hydrogen, alkyl, or optionally substituted aryl, and R29 is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplary guanidino groups include -NH- C(C=NH)-NH2, -NH-C(C=NCN)-NH2, and -NH-C(C=NH)-NHCH3. [0193] For the purpose of the present disclosure, the term "(heterocyclo)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclo groups. In one embodiment, the (heterocyclo)alkyl is a C1-4 alkyl substituted with one optionally substituted heterocyclo group. The heterocyclo can be linked to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include:
Figure imgf000242_0001
.
[0194] For the purpose of the present disclosure, the term "(heteroaryl)alkyl" or "heteroaralkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups. In one embodiment, the (heteroaryl)alkyl group is a C1-4 alkyl substituted with one optionally substituted heteroaryl group. Non-limiting exemplary (heteroaryl)alkyl groups include: ,
Figure imgf000242_0002
.
[0195] For the purpose of the present disclosure, the term "alkylcarbonylamino" as used by itself or as part of another group refers to an alkylcarbonyl group attached to an amino. A non-limiting exemplary alkylcarbonylamino group is -NHCOCH3. [0196] For the purpose of the present disclosure, the term "C1-4 bridge" refers to a -CH2-, -(CH2)2-, -(CH2)3-, or -(CH2)4- group that joins two carbon atoms of a piperidine to form an azabicyclo group. For example, in Formula I, R3a and R4a of B can be taken together to form a 6-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, or 10-azabicyclo[4.3.1]decane group. Each methylene unit of the C1-4 bridge can be optionally substituted with one or two substituents independently selected from the group consisting of C1-4 alkyl and halo.
[0197] The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H (or deuterium (D)), 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively, e.g., 3H, 11C, and 14C. In one embodiment, provided is a composition wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. In another embodiment, provided is a composition wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a position with an atom having a different atomic mass or mass number." Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.
[0198] Compounds of the Disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.
[0199] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers). [0200] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.
[0201] The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
[0202] The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive. In one embodiment, Compounds of the Disclosure are racemic.
[0203] The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.
[0204] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.
[0205] The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as ŇR - SŇ*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([D]obs/[D]max)*100, where [D]obs is the optical rotation of the mixture of enantiomers and [D]max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.
[0206] The terms "enantiomerically pure" or "enantiopure" refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense. In one embodiment, Compounds of the Disclosure are enantiomerically pure.
[0207] The terms "enantiomerically enriched" or "enantioenriched" refer to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50. In one embodiment, Compounds of the Disclosure are enantiomerically enriched, e.g., the enantiomeric ratio is about 60:40 or greater, about 70:30 or greater, about 80:20 or greater, about 90:10 or greater, about 95:5 or greater, about 98:2 or greater, or about 99:1 or greater. Enantiomerically enriched compounds may be enantiomerically pure.
[0208] The terms "a" and "an" refer to one or more. [0209] The term "about," as used herein, includes the recited number ± 10%. Thus, "about 10" means 9 to 11.
[0210] The present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as arginate, asparginate, glutamate and the like. The term "pharmaceutically acceptable salt" as used herein, refers to any salt, e.g., obtained by reaction with an acid or a base, of a Compound of the Disclosure that is physiologically tolerated in the target patient (e.g., a mammal, e.g., a human).
[0211] Acid addition salts can be formed by mixing a solution of the particular Compound of the Disclosure with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or the like. Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
[0212] The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A.L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.
[0213] Since Compounds of the Disclosure are inhibitors of SMYD proteins, such as SMYD3 and SMYD2, a number of diseases, conditions, or disorders mediated by SMYD proteins, such as SMYD3 and SMYD2, can be treated by employing these compounds. The present disclosure is thus directed generally to a method for treating a disease, condition, or disorder responsive to the inhibition of SMYD proteins, such as SMYD3 and SMYD2, in an animal suffering from, or at risk of suffering from, the disorder, the method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.
[0214] The present disclosure is further directed to a method of inhibiting SMYD proteins in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure. [0215] The present disclosure is further directed to a method of inhibiting SMYD3 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
[0216] The present disclosure is further directed to a method of inhibiting SMYD2 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
[0217] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms "treat," "treating," "treatment," and the like may include "prophylactic treatment," which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need of such treatment.
[0218] Within the meaning of the disclosure, "treatment" also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
[0219] The term "therapeutically effective amount" or "effective dose" as used herein refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to an individual in need thereof. In the case of a cancer or other proliferation disorder, the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; modulate protein methylation in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer. To the extent the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
[0220] The term "container" means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
[0221] The term "insert" means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the "label" for a pharmaceutical product.
[0222] The term "disease" or "condition" or "disorder" denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions. As demonstrated below, Compounds of the Disclosure inhibit SMYD proteins, such as SMYD3 and SMYD2 and can be used in treating diseases and conditions such as proliferative diseases, wherein inhibition of SMYD proteins, such as SMYD3 and SMYD2 provides a benefit.
[0223] In some embodiments, the Compounds of the Disclosure can be used to treat a "SMYD protein mediated disorder" (e.g., a SMYD3-mediated disorder or a SMYD2-mediated disorder). A SMYD protein mediated disorder is any pathological condition in which a SMYD protein is know to play a role. In some embodiments, a SMYD-mediated disorder is a proliferative disease.
[0224] In some embodiments inhibiting SMYD proteins, such as SMYD3 and SMYD2, is the inhibition of the activity of one or more activities of SMYD proteins such as SMYD3 and SMYD2. In some embodiments, the activity of the SMYD proteins such as SMYD3 and SMYD2 is the ability of the SMYD protein such as SMYD3 or SMYD2 to transfer a methyl group to a target protein (e.g., histone). It should be appreciated that the activity of the one or more SMYD proteins such as SMYD3 and SMYD2 may be inhibited in vitro or in vivo. Examplary levels of inhibition of the activity one or more SMYD proteins such as SMYD3 and SMYD2 include at least 10% inhibition, at least 20% inhibition, at least 30% inhibition, at least 40% inhibition, at least 50% inhibition, at least 60% inhibition, at least 70% inhibition, at least 80% inhibition, at least 90% inhibition, and up to 100% inhibition. [0225] The SMYD (SET and MYND domain) family of lysine methyltransferases (KMTs) plays pivotal roles in various cellular processes, including gene expression regulation and DNA damage response. The family of human SMYD proteins consists of SMYD1, SMYD2, SMYD3, SMYD4 and SMYD5. SMYD1, SMYD2, and SMYD3 share a high degree of sequence homology and, with the exception of SMYD5, human SMYD proteins harbor at least one C-terminal tetratrico peptide repeat (TPR) domain. (See e.g., Abu-Farha et al. J Mol Cell Biol (2011) 3 (5) 301-308). The SMYD proteins have been found to be linked to various cancers (See e.g., Hamamoto et al. Nat Cell. Biol. 2004, 6: 731-740), Hu et al. Canncer Research 2009, 4067-4072, and Komatsu et al. Carcinogenesis 2009, 301139-1146.)
[0226] SMYD3 is a protein methyltransferase found to be expressed at high levels in a number of different cancers (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004)). SMYD3 likely plays a role in the regulation of gene transcription and signal transduction pathways critical for survival of breast, liver, prostate and lung cancer cell lines (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Hamamoto, R., et al., Cancer Sci., 97(2):113-8 (2006); Van Aller, G.S., et al., Epigenetics, 7(4):340-3 (2012); Liu, C., et al., J. Natl. Cancer Inst., 105(22):1719-28 (2013); Mazur, P.K., et al., Nature, 510(7504):283-7 (2014)).
[0227] Genetic knockdown of SMYD3 leads to a decrease in proliferation of a variety of cancer cell lines (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Hamamoto, R., et al., Cancer Sci., 97(2):113-8 (2006); Van Aller, G.S., et al., Epigenetics, 7(4):340- 3 (2012); Liu, C., et al., J. Natl. Cancer Inst., 105(22):1719-28 (2013); Mazur, P.K., et al., Nature, 510(7504):283-7 (2014)). Several studies employing RNAi-based technologies have shown that ablation of SMYD3 in hepatocellular carcinoma cell lines greatly reduces cell viability and that its pro-survival role is dependent on its catalytic activity (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Van Aller, G.S., et al., Epigenetics, 7(4):340-3 (2012)). Moreover, SMYD3 has also been shown to be a critical mediator of transformation resulting from gain of function mutations in the oncogene, KRAS for both pancreatic and lung adenocarcinoma in mouse models. The dependence of KRAS on SMYD3 was also shown to be dependent on its catalytic activity (Mazur, P.K., et al., Nature, 510(7504):283-7 (2014)). SMYD3 function has also been implicated in colerectal cancers and RNAi mediated knockdown of SMYD3 has been shown to impair colerectal cell proliferation. (Peserico et al., Cell Physiol. 2015 Feb 28. doi: 10.1002/jcp.24975. [Epub ahead of print]).
[0228] Furthermore, SMYD3 function has also been shown to play a role in immunology and development. For instance, de Almeida reported that SMYD3 plays a role in generation of inducible regulatory T cells (iTreg) cells. In a mouse model of respiratory syncytial virus (RSV) infection, a model in which iTreg cells have a critical role in regulating lung pathogenesis, SMYD3-/- mice demonstrated exacerbation of RSV- induced disease related to enhanced proinflammatory responses and worsened pathogenesis within the lung (de Almeida et al. Mucosal Immunol. 2015 Feb 11. doi: 10.1038/mi.2015.4. [Epub ahead of print]). In addition, as to development, Proserpio et al. have shown the importance of SMYD3 in the regulation of skeletal muscle atrophy (Proserpio et al. Genes Dev. 2013 Jun 1;27(11):1299-312), while Fujii et al. have elucidated the role of SMYD3 in cardiac and skeletal muscle development (Fujii et al. PLoS One. 2011;6(8):e23491).
[0229] SMYD2 (SET and MYND domain-containing protein 2) was first characterized as protein that is a member of a sub-family of SET domain containing proteins which catalyze the site-specific transfer of methyl groups onto substrate proteins. SMYD2 was initially shown to have methyltransferase activity towards lysine 36 on histone H3 (H3K36) but has subsequently been shown to have both histone and non-histone methyltrasferase activity.
[0230] SMYD2 has been implicated in the pathogenesis of multiple cancers. It has been shown to be over-expressed, compared to matched normal samples, in tumors of the breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus and prostate, as well as hematologic malignancies such as AML, B- and T-ALL, CLL and MCL, suggesting a role for SMYD2 in the biology of these cancers. More specifically, studies using genetic knock-down of SMYD2 have demonstrated anti-proliferative effects in esophageal squamous cell carcinoma (ESCC), bladder carcinoma and cervical carcinoma cell lines. (See e.g., Komatsu et al., Carcinogenesis 2009, 30, 1139, and Cho et al., Neoplasia. 2012 Jun;14(6):476-86). Moreover, high expression of SMYD2 has been shown to be a poor prognostic factor in both ESCC and pediatric ALL. (See e.g., Komatsu et al. Br J Cancer. 2015 Jan 20;112(2):357-64, and Sakamoto et al., Leuk Res. 2014 Apr;38(4):496-502). Recently, Nguyen et al., have shown that a small molecule inhibitor of SMYD2 (LLY-507) inhibited the proliferation of several esophageal, liver and breast cancer cell lines in a dose-dependent manner. (Nguyen et al. J Biol Chem. 2015 Mar 30. pii: jbc.M114.626861. [Epub ahead of print]).
[0231] SMYD2 has also been implicated in immunology. For instance, Xu et al. have shown that SMYD2 is a negative regulator of macrophage activation by suppressing Interleukin-6 and TNF-alpha production. (Xu et al., J Biol Chem. 2015 Feb 27;290(9):5414-23).
[0232] In one aspect, the present disclosure provides a method of treating cancer in a patient comprising administering a therapeutically effective amount of a Compound of the Disclosure. While not being limited to a specific mechanism, in some embodiemtns, Compounds of the Disclorure can treat cancer by inhibiting SMYD proteins, such as SMYD3 and SMYD2. Examples of treatable cancers include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B- cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
[0233] In another embodiment, the cancer is breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus, or prostate cancer.
[0234] In another embodiment, the cancer is a hematologic malignancy such as acute myeloid leukemia (AML), B- and T-acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma (MCL).
[0235] In another embodiment, the cancer is esophageal squamous cell carcinoma (ESCC), bladder carcinoma, or cervical carcinoma.
[0236] In another embodiment, the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL). In another embodiment the cancer is NUT-midline carcinoma. In another embodiment the cancer is multiple myeloma. In another embodiment the cancer is a lung cancer such as small cell lung cancer (SCLC). In another embodiment the cancer is a neuroblastoma. In another embodiment the cancer is Burkitt's lymphoma. In another embodiment the cancer is cervical cancer. In another embodiment the cancer is esophageal cancer. In another embodiment the cancer is ovarian cancer. In another embodiment the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.
[0237] In another embodiment, the present disclosure provides a therapeutic method of modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in the cancers mentioned above by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such therapy.
[0238] Compounds of the Disclosure can be administered to a mammal in the form of a raw chemical without any other components present. Compounds of the Disclosure can also be administered to a mammal as part of a pharmaceutical composition containing the compound combined with a suitable pharmaceutically acceptable carrier. Such a carrier can be selected from pharmaceutically acceptable excipients and auxiliaries. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.
[0239] Pharmaceutical compositions within the scope of the present disclosure include all compositions where a Compound of the Disclosure is combined with one or more pharmaceutically acceptable carriers. In one embodiment, the Compound of the Disclosure is present in the composition in an amount that is effective to achieve its intended therapeutic purpose. While individual needs may vary, a determination of optimal ranges of effective amounts of each compound is within the skill of the art. Typically, a Compound of the Disclosure can be administered to a mammal, e.g., a human, orally at a dose of from about 0.0025 to about 1500 mg per kg body weight of the mammal, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, per day to treat the particular disorder. A useful oral dose of a Compound of the Disclosure administered to a mammal is from about 0.0025 to about 50 mg per kg body weight of the mammal, or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof. For intramuscular injection, the dose is typically about one-half of the oral dose.
[0240] A unit oral dose may comprise from about 0.01 mg to about 1 g of the Compound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about 50 mg, e.g., about 0.1 mg to about 10 mg, of the compound. The unit dose can be administered one or more times daily, e.g., as one or more tablets or capsules, each containing from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.
[0241] A pharmaceutical composition of the present disclosure can be administered to any patient that may experience the beneficial effects of a Compound of the Disclosure. Foremost among such patients are mammals, e.g., humans and companion animals, although the disclosure is not intended to be so limited. In one embodiment, the patient is a human.
[0242] A pharmaceutical composition of the present disclosure can be administered by any means that achieves its intended purpose. For example, administration can be by the oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or buccal route, or by inhalation. The dosage administered and route of administration will vary, depending upon the circumstances of the particular subject, and taking into account such factors as age, gender, health, and weight of the recipient, condition or disorder to be treated, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
[0243] In one embodiment, a pharmaceutical composition of the present disclosure can be administered orally. In another embodiment, a pharmaceutical composition of the present disclosure can be administered orally and is formulated into tablets, dragees, capsules, or an oral liquid preparation. In one embodiment, the oral formulation comprises extruded multiparticulates comprising the Compound of the Disclosure.
[0244] Alternatively, a pharmaceutical composition of the present disclosure can be administered rectally, and is formulated in suppositories.
[0245] Alternatively, a pharmaceutical composition of the present disclosure can be administered by injection.
[0246] Alternatively, a pharmaceutical composition of the present disclosure can be administered transdermally.
[0247] Alternatively, a pharmaceutical composition of the present disclosure can be administered by inhalation or by intranasal or transmucosal administration.
[0248] Alternatively, a pharmaceutical composition of the present disclosure can be administered by the intravaginal route.
[0249] A pharmaceutical composition of the present disclosure can contain from about 0.01 to 99 percent by weight, e.g., from about 0.25 to 75 percent by weight, of a Compound of the Disclosure, e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a Compound of the Disclosure.
[0250] A pharmaceutical composition of the present disclosure is manufactured in a manner which itself will be known in view of the instant disclosure, for example, by means of conventional mixing, granulating, dragee-making, dissolving, extrusion, or lyophilizing processes. Thus, pharmaceutical compositions for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. [0251] Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
[0252] Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. Dragee cores are provided with suitable coatings that are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
[0253] Examples of other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, or soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain a compound in the form of granules, which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers, or in the form of extruded multiparticulates. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers can be added.
[0254] Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases include natural and synthetic triglycerides, and paraffin hydrocarbons, among others. It is also possible to use gelatin rectal capsules consisting of a combination of active compound with a base material such as, for example, a liquid triglyceride, polyethylene glycol, or paraffin hydrocarbon.
[0255] Suitable formulations for parenteral administration include aqueous solutions of the active compound in a water-soluble form such as, for example, a water-soluble salt, alkaline solution, or acidic solution. Alternatively, a suspension of the active compound can be prepared as an oily suspension. Suitable lipophilic solvents or vehicles for such as suspension may include fatty oils (for example, sesame oil), synthetic fatty acid esters (for example, ethyl oleate), triglycerides, or a polyethylene glycol such as polyethylene glycol-400 (PEG-400). An aqueous suspension may contain one or more substances to increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. The suspension may optionally contain stabilizers.
[0256] In another embodiment, the present disclosure provides kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure. In one embodiment, the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration. General Synthesis of Compounds
[0257] Compounds of the Disclosure are prepared using methods known to those skilled in the art in view of this disclosure, or by the illustrative methods shown in the General Schemes below. In the General Schemes, R1, R2a, R3b, R3b, R4a, R5a, and Z of Formulae A-D are as defined in connection with Formula I, unless otherwise indicated. In any of the General Schemes, suitable protecting can be employed in the synthesis, for example, when Z is (amino)alkyl or any other group that may group that may require protection, or when R8 is amino, (amino)alkyl, or any other group that may requie protection. (See, Wuts, P. G. M.; Greene, T. W., "Greene's Protective Groups in Organic Synthesis", 4th Ed., J. Wiley & Sons, NY, 2007). General Scheme 1
Figure imgf000258_0001
[0258] Compound A is converted to compound B (i.e, a compound having Formula I, wherein R2b, R3b, R4b, R5b, and R6 are each hydrogen, and X is -S(=O)2-) by coupling with a suitable sulfonyl chloride (Z-SO2Cl) in the presence of a suitable base such as TEA or DIPEA in a suitable solvent such as dichloromethane, acetonitrile, or DMF.
General Scheme 2
Figure imgf000258_0002
[0259] Compound A is converted to compound C (i.e, a compound having Formula I, wherein R2b, R3b, R4b, R5b, and R6 are each hydrogen, and X is -C(=O)-) by coupling with a suitable acide chloride (Z-COCl) in the presence of a suitable base such as TEA or DIPEA in a suitable solvent such as dichloromethane, acetonitrile, or DMF, or by coupling with a suitable carboxylic acid (Z-CO2H) in the presence of a suitable coupling reagent such as HATU and a suitable base such as TEA or DIPEA in a suitable solvent such as dichloromethane, acetonitrile, or DMF.
General Scheme 3
Figure imgf000258_0003
[0260] Compound A is converted to compound D (i.e, a compound having Formula I, wherein R2b, R3b, R4b, R5b, and R6 are each hydrogen, and X is -C(=O)C(R8)(H)-) by coupling with a suitable carboxylic acid (Z-C(H)R8-CO2H) in the presence of a suitable coupling reagent such as HATU and a suitable base such as TEA or DIPEA in a suitable solvent such as dichloromethane, acetonitrile, or DMF. EXAMPLES General Synthetic Methods [0261] General methods and experimental procedures for preparing and characterizing compounds of Tables 1-3 are set forth in the general schemes above and the examples below. Wherever needed, reactions were heated using conventional hotplate apparatus or heating mantle or microwave irradiation equipment. Reactions were conducted with or without stirring, under atmospheric or elevated pressure in either open or closed vessels. Reaction progress was monitored using conventional techniques such as TLC, HPLC, UPLC, or LCMS using instrumentation and methods described below. Reactions were quenched and crude compounds isolated using conventional methods as described in the specific examples provided. Solvent removal was carried out with or without heating, under atmospheric or reduced pressure, using either a rotary or centrifugal evaporator.
[0262] Compound purification was carried out as needed using a variety of traditional methods including, but not limited to, preparative chromatography under acidic, neutral, or basic conditions using either normal phase or reverse phase HPLC or flash columns or Prep-TLC plates. Compound purity and mass confirmations were conducted using standard HPLC and / or UPLC and / or MS spectrometers and / or LCMS and / or GC equipment (i.e., including, but not limited to the following instrumentation: Waters Alliance 2695 with 2996 PDA detector connected with ZQ detector and ESI source; Shimadzu LDMS-2020; Waters Acquity H Class with PDA detector connected with SQ detector and ESI source; Agilent 1100 Series with PDA detector; Waters Alliance 2695 with 2998 PDA detector; AB SCIEX API 2000 with ESI source; Agilent 7890 GC). Exemplified compounds were dissolved in either MeOH or MeCN to a concentration of approximately 1 mg/mL and analyzed by injection of 0.5-10 μL into an appropriate LCMS system using the methods provided in the following table. In each case the flow rate is 1 mL/min. LCMS data are presented in Tables 1A, 2A, and 3A.
Figure imgf000260_0001
[0263] Compound structure confirmations were carried out using standard 300 or 400 MHz NMR spectrometers with nOe's conducted whenever necessary.
[0264] The following abbreviations are used herein:
Figure imgf000261_0001
Figure imgf000262_0004
EXAMPLE 1
Synthesis of 5-cyclopropylisoxazole-3-carboxylic acid
Figure imgf000262_0001
Step 1: Synthesis of ethyl 4-cyclopropyl-2,4-dioxobutanoate
Figure imgf000262_0002
[0265] Into a 10-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen Na (164 g, 1.20 equiv) was added in portions to ethanol (5 L). A solution of (CO2Et)2 (869 g, 1.00 equiv) and 1-cyclopropylethan-1-one (500 g, 5.94 mol, 1.00 equiv) was added dropwise with stirring at 0-20oC. The resulting solution was stirred for 1 h at 20-30o C and then for an additional 1 h at 80oC. The resulting solution was diluted with 15 L of H2O. The pH was adjusted to 2 with hydrochloric acid (12N). The resulting solution was extracted with ethyl acetate and the organic layers combined and washed with NaHCO3 (sat. aq.). The extract was concentrated under vacuum yielding 820 g (crude) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.5.
Step 2: Synthesis of ethyl 5-cyclopropylisoxazole-3-carboxylate
Figure imgf000262_0003
[0266] Into a 10 L round-bottom flask, was placed a solution of ethyl 4-cyclopropyl-2,4- dioxobutanoate (177 g) in ethanol (1.1 L) and NH2OH-HCl (200 g). The resulting solution was stirred for 1 h at 20-30oC. The resulting solution was allowed to react, with stirring, for an additional 1 h at 80oC. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 143 g (the two step yield was 66.3%) of ethyl 5- cyclopropylisoxazole-3-carboxylate as a yellow oil. TLC (ethyl acetate/petroleum ether =1/5): Rf = 0.2.
Step 3: Synthesis of 5-cyclopropylisoxazole-3-carboxylic acid
Figure imgf000263_0001
[0267] Into a 10-L round-bottom flask was placed ethyl 5-cyclopropylisoxazole-3- carboxylate (280 g, 1.55 mol, 1.00 equiv) and a solution of sodium hydroxide (74.3 g, 1.20 equiv) in water (4 L). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with ether. The pH value of the aqueous solution was adjusted to 2-3 with hydrochloric acid (12N). The resulting solution was extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 220 g (93%) of 5-cyclopropylisoxazole-3-carboxylic acid as an off-white solid. LCMS (method A, ESI): RT = 1.99 min, m/z = 153.9 [M+H]+. 1H-NMR (300 MHz CDCl3): 8.42(brs, 1H), 6.37(s, 1H), 2.16-2.05(m, 1H), 1.29-1.12(m, 2H), 1.12-0.99(m, 2H) ppm.
EXAMPLE 2
Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide hydrochloride and 5-cyclopropyl-N-((2S,4R)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide h drochloride
Figure imgf000263_0002
Step 1: Synthesis of (2S)-tert-butyl 4-amino-2-methylpiperidine-1-carboxylate
Figure imgf000263_0003
[0268] Into a 10-L round-bottom flask was placed methanol (5 L), HCOONH4 (190 g, 3.01 mol, 37.80 equiv), acetic acid (5 g, 83.26 mmol, 1.04 equiv) and tert-butyl (2S)-2- methyl-4-oxopiperidine-1-carboxylate (17 g, 79.71 mmol, 1.00 equiv). Then NaBH3CN (10 g, 159.13 mmol, 2.00 equiv) was added batchwise. The resulting solution was stirred at 25oC overnight. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 500 mL of ethyl acetate. The resulting solution was washed with 3x500 mL of brine (sat.). This resulted in 15.5 g (91%) of tert-butyl (2S)-4-amino-2- methylpiperidine-1-carboxylate as off-white oil. LCMS (method A, ESI): RT=1.21min, m/z =215.1 [M+H]+.
Step 2: Synthesis of (2S)-tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-2- methylpiperidine-1-carboxylate
Figure imgf000264_0001
[0269] Into a 1L round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed dichloromethane (500 mL), HOBT (15 g, 111.01 mmol, 1.53 equiv), EDCI (20 g, 104.33 mmol, 1.44 equiv), 5-cyclopropyl-1,2-oxazole-3-carboxylic acid (13.3 g, 86.85 mmol, 1.20 equiv) and tert-butyl (2S)-4-amino-2-methylpiperidine-1- carboxylate (15.5 g, 72.33 mmol, 1.00 equiv).Then triethylamine (36 g, 355.77 mmol, 4.92 equiv) was added dropwise. The resulting solution was stirred for 2 hours at 25oC. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 500 mL of ethyl acetate. The resulting mixture was washed with 3x500 mL of water. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 14 g (55%) of tert-butyl (2S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidine-1-carboxylate as light yellow oil. LCMS (method A, ESI): RT=2.05 min, m/z =350.2 [M+H]+.
Step 3: Synthesis of tert-butyl (2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidine-1-carboxylate and tert-butyl (2S,4R)-4-(5-cyclopropyl-1,2-oxazole-3- amido)-2-methylpiperidine-1-carboxylate
Figure imgf000264_0002
[0270] The crude product was purified by Chrial-HPLC with the following conditions:
Column name: CHIRALPAK AD-H, 4.6*150mm,5um,Co-Solvent: EtOH(0.1%DEA), %Co-Solvent: Hexane,25.000, Detector: 220nm. The resulting solution was concentrated under vacuum. This resulted in 9.8 g (70%) of tert-butyl (2S,4S)-4-(5-cyclopropyl-1,2- oxazole-3-amido)-2-methylpiperidine-1-carboxylate as white solid. 1H-NMR (400 MHz, DMSO): į 8.54-8.52 (m, 1H), 6.47 (s, 1H), 3.94-3.87(m, 2H), 3.57-3.53(m, 1H), 3.32- 3.26(m, 1H), 2.20-2.16(m, 1H), 1.80-1.63(m, 4H), 1.39(s, 9H), 1.16-1.15(m, 3H), 1.10- 1.06(m, 2H), 0.93-0.89(m, 2H) ppm. And 3.3 g (24%) of tert-butyl (2S,4R)-4-(5- cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate as a light yellow solid. 1H-NMR (400 MHz, DMSO): į 8.54-8.52 (m, 1H), 6.46 (s, 1H), 4.54-4.30(m, 1H), 4.28-4.04(m, 1H), 4.00-3.68(m, 1H), 3.10-2.70(m, 1H), 2.19-2.15(m, 1H), 1.76-1.73(m, 1H), 1.63-1.59(m, 2H), 1.39-1.35(m, 10H), 1.13-1.08(m, 5H),1.00-0.82(m, 2H) ppm.
Step 4: Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole- 3-carboxamide hydrochloride and 5-cyclopropyl-N-((2S,4R)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide hydrochloride
Figure imgf000265_0001
[0271] Into a 250-mL round-bottom flask was placed dichloromethane (100 mL), tert- butyl (2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate (9.8 g, 28.05 mmol, 1.00 equiv). To the above hydrogen chloride was introduced. The resulting solution was stirred for 2 hours at 25oC. The resulting mixture was concentrated under vacuum. This resulted in 8.6 g of 5-cyclopropyl-N-[(2S,4S)-2-methylpiperidin-4- yl]-1,2-oxazole-3-carboxamide hydrochloride as a white solid. 1HNMR (400 MHz, MeOD): į 6.40(s, 1H), 4.24-4.10(m, 1H), 3.55-3.45(m, 1H), 3.40-3.35(m, 1H), 3.19- 3.15(m, 1H), 2.24-2.15(m, 3H), 1.82-1.77(m, 1H), 1.63-1.60(m, 1H), 1.93-1.37(m, 3H), 1.21-1.13(m, 2H), 1.00-0.96(m, 2H) ppm. LCMS (method A, ESI): RT=1.13 min, m/z =250.1 [M-HCl+H]+.
Figure imgf000265_0002
[0272] Into a 100-mL round-bottom flask was placed dichloromethane (50 mL), tert- butyl (2S,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate (3.3 g, 9.44 mmol, 1.00 equiv). To the above hydrogen chloride was introduced. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 3 g (crude) of 5-cyclopropyl-N-[(2S,4R)-2- methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide hydrochloride as a light yellow solid. 1H NMR (400 MHz, MeOD): į6.41(s, 1H), 4.36-4.34(m, 1H), 3.62-3.59(m, 1H), 3.40- 3.35(m, 2H), 2.21-2.03(m, 4H), 1.90-1.82(m, 1H), 1.39-1.37(m, 3H), 1.18-1.14(m, 2H), 1.00-0.96(m,2H) ppm. LCMS (method A, ESI): RT=1.03 min, m/z =250.1 [M-HCl+H]+. EXAMPLE 3
Synthesis of 5-cyclopropyl-N-((2R,4R)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide hydrochloride and 5-cyclopropyl-N-((2R,4S)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide h drochloride
Figure imgf000266_0001
Step 1: Synthesis of (2R)-tert-butyl 4-amino-2-methylpiperidine-1-carboxylate
Figure imgf000266_0002
[0273] Into a 5000-mL round-bottom flask was placed tert-butyl (2R)-2-methyl-4- oxopiperidine-1-carboxylate (8.53 g, 40.00 mmol, 1.00 equiv), HCOONH4 (100.8 g, 1.60 mol, 39.97 equiv), methanol (4 L) and acetic acid (2.4 g, 39.97 mmol, 1.00 equiv). Then NaBH3CN (5.04 g, 80.00 mmol, 2.00 equiv) was added batchwise. The resulting solution was stirred for 15 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of brine (sat.). The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine and concentrated under vacuum. This resulted in 10.5 g (98%) of tert-butyl (2R)-4-amino-2-methylpiperidine-1- carboxylate as a white solid. LCMS (method A, ESI): RT=1.06min, m/z =159.0 [M-56+H]+. \
Step 2: Synthesis of (2R,4R)-tert-butyl 4-(5-cyclopropylisoxazole-3- carboxamido)-2-methylpiperidine-1-carboxylate and (2R,4S)-tert-butyl 4-(5- cyclopropylisoxazole-3-carboxamido -2-meth l i eridine-1-carbox late
Figure imgf000266_0003
[0274] Into a 500-mL round-bottom flask was placed 5-cyclopropyl-1,2-oxazole-3- carboxylic acid (6.12 g, 39.96 mmol, 1.00 equiv), tert-butyl (2R)-4-amino-2- methylpiperidine-1-carboxylate (8.57 g, 39.99 mmol, 1.00 equiv), dichloromethane (300 g), TEA (12.12 g, 120.00 mmol, 3.00 equiv) and HATU (22.8 g, 60.00 mmol, 1.50 equiv). The resulting solution was stirred for 15 h at room temperature. The resulting mixture was then washed with 2x100mL of Na2CO3 (1M, aq.). Then the organic phase was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (C18 gel, CH3CN/H2O = 1:1) to give 10.8 g diastereomeric tert- butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-2-methylpiperidine-1-carboxylate. Then the purified product was separated by Prep-SFC with the following conditions (prep SFC 350): Column, CHIRALPAK AD-H SFC, 5x25cm,5um; mobile phase, CO2(50%), methanol(50%); Detector, uv 220nm. This was resulted in 7.48 g (54%) of tert-butyl (2R,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate as light yellow oil. 1H-NMR (300 MHz, CDCl3): 6.86 (d, J = 6.9 Hz, 1H), 6.33 (s, 1H), 4.30-4.15 (m, 2H), 3.93-3.80(m, 1H), 3.22-3.07(m, 1H), 2.20-1.90 (m, 3H), 1.79-1.65(m, 2H), 1.46(s, 9H), 1.26(d, J = 6.9 Hz, 3H), 1.17-1.06(m, 2H), 1.06-0.94(m, 2H) ppm. LCMS (method A, ESI): RT=1.46 min, m/z =372.2 [M+H]+. And 2.52 g (18%) of tert- butyl (2R,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate as a light yellow solid. 1H-NMR (300 MHz, CDCl3): į 6.55 (d, J = 8.1 Hz, 1H), 6.33 (s, 1H), 4.63-4.39 (m, 1H), 4.39-4.15(m, 1H), 4.15-3.95(m, 1H), 3.0-2.85 (m, 1H), 2.15- 1.98(m, 2H), 1.92-1.78(m, 1H), 1.65-1.50 (m, 1H), 1.46(s, 9H), 1.42-1.26 (m, 1H), 1.23(d, J = 6.9 Hz, 3H), 1.17-1.06(m, 2H), 1.06-0.94(m, 2H) ppm. LCMS (method A, ESI): RT=1.46 min, m/z =372.2 [M+H]+.
Step 3: Synthesis of 5-cyclopropyl-N-((2R,4R)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide h drochloride
Figure imgf000267_0001
[0275] Into a 250-mL round-bottom flask was placed tert-butyl (2R,4R)-4-(5- cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate (7.48 g, 21.41 mmol, 1.00 equiv) and 1,4-dioxane (50 mL). Then hydrogen chloride was introduced into mixture. The resulting solution was stirred for 15 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 6.03 g (99%) of 5-cyclopropyl- N-[(2R,4R)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide hydrochloride as a white solid. LCMS (method D, ESI): RT=0.58 min, m/z =250.0 [M+H]+.
Step 4: Synthesis of 5-cyclopropyl-N-((2R,4S)-2-methylpiperidin-4-yl)isoxazole- 3-carboxamide hydrochloride
Figure imgf000268_0001
[0276] Into a 100-mL round-bottom flask was placed tert-butyl (2R,4S)-4-(5- cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate (2.52 g, 7.21 mmol, 1.00 equiv) and 1,4-dioxane (15 mL). Then hydrogen chloride was introduced into mixture. The resulting solution was stirred for 15 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 2.0 g (97%) of 5-cyclopropyl- N-[(2R,4S)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide hydrochloride as a light yellow solid. LCMS (method A, ESI): RT=1.12 min, m/z =250.0 [M+H]+. EXAMPLE 4
Synthesis of N-((2S,4S)-2-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide h drochloride salt
Figure imgf000268_0002
Step 1: Synthesis of tert-butyl 4-amino-2-benzylpiperidine-1-carboxylate
Figure imgf000268_0003
[0277] Into a 5-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl 2-benzyl-4-oxopiperidine-1-carboxylate (5 g, 17.28 mmol, 1.00 equiv), methanol (4 L), acetic acid (2.076 g, 34.57 mmol, 2.00 equiv) and HCOONH4 (43.599 g). The resulting solution was stirred for 0.5 h at room temperature. Then NaBH3CN (2.180 g, 34.69 mmol, 2.01 equiv) was added by batchwise. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of EA. The resulting mixture was washed with 4x100 mL of brine (sat.). The organic phase was collected and concentrated under vacuum. The solid was dried in an oven under reduced pressure. This resulted in 5 g (100%) of tert-butyl 4-amino-2-benzylpiperidine-1- carboxylate as light yellow oil. LCMS (method C, ESI): RT =0.89 min, m/z =235.0 [M- 56+H]+.
Step 2: Synthesis of (2R,4R)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3- carboxamido)piperidine-1-c
Figure imgf000269_0001
;
(2S,4S)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1- carboxylate
Figure imgf000269_0002
;
(2S,4R)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1- carbox late
Figure imgf000269_0003
; and
(2R,4S)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1- carboxylate
Figure imgf000270_0001
[0278] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl 4-amino-2-benzylpiperidine-1-carboxylate (5 g, 17.22 mmol, 1.00 equiv), dichloromethane (100 mL), TEA (8.707 g, 86.05 mmol, 5.00 equiv), 5-cyclopropyl-1,2-oxazole-3-carboxylic acid (3.957 g, 25.84 mmol, 1.50 equiv), HATU (19.655 g, 51.69 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of EA. The resulting mixture was washed with 3x200 mL of brine (sat.). The organic phase was collected and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). The collected fractions were combined and concentrated under vacuum. The crude product 2.9 g was purified by Prep-SFC with the following conditions (prep SFC 350-2): Column, Chiralpak AD-H, 5x25cm, 5um; mobile phase, CO2(70%), IPA(30%) and DCM/MeOH=1/3:100 ; Detector, uv 210nm yielding two fractions: first peak - cis enantiomers 1.7 g, second peak trans enantiomers 0.6 g.
[0279] These products were further purified by SFC. The cis mixtures were purified by Prep-SFC with the following conditions (prep SFC 350-2): Column, Chiralpak AS-H, 5*25cm, 5um; mobile phase, CO2 (70%), IPA (30%) and MeOH (50%); Detector, uv 210nm. This resulted in 820 mg of (2R,4R)-tert-butyl 2-benzyl-4-(5- cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate as yellow oil and 870 mg of(2S,4S)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1- carboxylate as yellow oil. (2R,4R)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3- carboxamido)piperidine-1-carboxylate: 1H-NMR (300 MHz, CD3Cl) į: 7.26-7.17(m, 5H), 6.88 (d, J = 6.9 Hz, 1H), 6.32(d, J = 0.6 Hz, 1H), 4.38-4.28 (m, 1H), 4.27-4.16 (m, 1H), 4.09-3.98(m, 1H), 3.18-2.99 (m, 2H), 2.82-2.75 (m,1H), 2.12-1.98(m, 2H), 1.91- 1.66 (m, 3H), 1.37(d, J = 2.7 Hz, 9H), 1.18-1.09 (m, 2H), 1.02-0.92 (m, 2H) ppm. LCMS (method A, ESI): RT =1.59 min, m/z =326.0 [M-Boc+H]+. (2S,4S)-tert-butyl 2-benzyl-4- (5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate: 1H-NMR (300 MHz, CD3Cl) į: 7.26-7.17(m, 5H), 6.88(d, J = 6.9 Hz, 1H), 6.32(d, J = 0.6Hz, 1H), 4.38-4.28 (m, 1H), 4.27-4.16 (m, 1H), 4.09-3.98(m, 1H), 3.18-2.99 (m, 2H), 2.82-2.75 (m, 1H), 2.12-1.98(m, 2H), 1.91-1.66 (m, 3H), 1.37(d, J = 2.7 Hz, 9H), 1.18-1.09(m, 2H), 1.02- 0.92(m, 2H) ppm. LCMS (method A, ESI): RT =1.59 min, m/z = 326.0 [M-Boc+H]+.
[0280] The trans mixture was purified by Prep-SFC with the following conditions (prep SFC 350): Column, Phenomenex Lux 5u Cellulose-4250*50mm00G-4491-V0- AX664184-1; mobile phase, CO2(50%) and MeOH(50%) ,Detector, uv 220 nm. This resulted in 250 mg of (2S,4R)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3- carboxamido)piperidine-1-carboxylate as yellow oil and 260 mg of (2R,4S)-tert-butyl 2- benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate as yellow oil. (2S,4R)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1- carboxylate: 1H-NMR (300 MHz, CD3Cl) į: 7.26-7.17(m, 5H), 6.88(d, J = 6.9 Hz, 1H), 6.32(s, 1H), 4.81-3.91 (m, 3H), 3.08(t, J = 13.5 Hz, 1H), 2.96-2.81(m, 2H), 2.11-2.02(m, 2H), 1.95(d, J = 10.5 Hz, 1H), 1.52-1.22(m, 11H), 1.15-1.05(m, 2H), 1.02-0.92(m, 2H) ppm. LCMS (method A, ESI): RT = 1.58 min, m/z = 448.0 [M+Na]+. (2R,4S)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate: 1H-NMR (300 MHz, CD3Cl) į: 7.26-7.17(m, 5H), 6.88(d, J = 6.9 Hz, 1H), 6.32(s, 1H), 4.81-3.91 (m, 3H), 3.08(t, J = 13.5 Hz, 1H), 2.96-2.81(m, 2H), 2.11-2.02(m, 2H), 1.95(d, J = 10.5 Hz, 1H), 1.52-1.22(m, 11H), 1.15-1.05(m, 2H), 1.02-0.92(m, 2H) ppm. LCMS (method A, ESI): RT = 1.58 min, m/z = 448.0 [M+Na]+.
Step 3: Synthesis of N-((2R,4R)-2-benzylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide h drochloride
Figure imgf000271_0001
;
N-((2S,4S)-2-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
hydrochloride
Figure imgf000272_0001
N-((2S,4R)-2-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
h drochloride
Figure imgf000272_0002
N-((2R,4S)-2-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
h drochloride
Figure imgf000272_0003
[0281] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl (2R,4R)-2-benzyl-4-(5-cyclopropyl-1,2- oxazole-3-amido)piperidine-1-carboxylate (820 mg, 1.93 mmol, 1.00 equiv) and 1,4- dioxane (20 mL). Then hydrogen chloride was introduced into mixture. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 670 mg (96%) of N-[(2R,4R)-2- benzylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride as a white solid. LCMS (method A, ESI): RT = 1.11 min, m/z = 326.0 [M+H]+.
[0282] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl (2S,4S)-2-benzyl-4-(5-cyclopropyl-1,2- oxazole-3-amido)piperidine-1-carboxylate (870 mg, 2.05 mmol, 1.00 equiv) and 1,4- dioxane (20 mL). Then hydrogen chloride was introduced into mixture. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 710 mg (96%) of N-[(2S,4S)-2- benzylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride as a white solid. LCMS (method A, ESI): RT = 1.10 min, m/z = 326.0 [M+H]+.
[0283] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl (2S,4R)-2-benzyl-4-(5-cyclopropyl-1,2- oxazole-3-amido)piperidine-1-carboxylate (250 mg, 0.59 mmol, 1.00 equiv) and 1,4- dioxane (10 mL). Then hydrogen chloride was introduced into mixture. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 190 mg (91%) of N-[(2S,4R)-2- benzylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride as a white solid. LCMS (method A, ESI): RT = 1.11 min, m/z = 326.0 [M+H]+.
[0284] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl (2R,4S)-2-benzyl-4-(5-cyclopropyl-1,2- oxazole-3-amido)piperidine-1-carboxylate (260 mg, 0.61 mmol, 1.00 equiv) and 1,4- dioxane (10 mL). Then hydrogen chloride was introduced into mixture. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (91%) of N-[(2R,4S)-2- benzylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride as a white solid. LCMS (method A, ESI): RT = 1.11 min, m/z = 326.0 [M+H]+. EXAMPLE 5
Synthesis of N-((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3- carboxamide
Figure imgf000273_0001
N-((1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000273_0002
Step 1: Synthesis of (1R,5S,E)-tert-butyl 3-(hydroxyimino)-9- azabicyclo[3.3.1]nonane-9-carboxylate
Figure imgf000274_0002
[0285] Into a 2000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (1R,5S)-tert-butyl 3-oxo-9- azabicyclo[3.3.1]nonane-9-carboxylate (25 g, 104.03 mmol, 1.00 equiv) in ethanol (500 mL) at room temperature. This was followed by the addition of hydroxylamine hydrochloride (14.5 g, 208.66 mmol, 2.01 equiv) at room temperature. To this was added a solution of sodium hydroxide (8.4 g, 210.00 mmol, 2.02 equiv) in water (250 mL) by dropwise with stirring at room temperature. The resulting solution was stirred for 8 h at 95oC. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 250 mL of H2O. The resulting solution was extracted with 3x250 mL of dichloromethane and the organic layers combined. The resulting solution was concentrated under vacuum. This resulted in 26 g (98%) of (1R,5S,E)-tert-butyl 3- (hydroxyimino)-9-azabicyclo[3.3.1]nonane-9-carboxylate as a white solid. 1H NMR (300 MHz, DMSO) G : 10.40(s, 1H), 4.29(s, 2H), 3.04(d, 1H), 2.44-2.27(m, 2H), 1.99(d, 1H), 1.79-1.58(m, 5H), 1.49-1.45 (m, 1H), 1.41(s, 9H) ppm. LCMS (Method D, ESI): RT=1.76 min, m/z =240.0 [M -15+H]+.
Step 2: Synthesis of (1R,3s,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9- carboxylate and (1R,3r,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate
Figure imgf000274_0001
[0286] Into a 5000-mL round-bottom flask was placed a solution of (1R,5S,E)-tert-butyl 3-(hydroxyimino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (26 g, 101.83 mmol, 1.00 equiv) in methanol (4500 mL) at room temperature. This was followed by the addition of Raney-Ni (13 g) at room temperature. The flask was evacuated and flushed three times with nitrogen, then followed by flushing with hydrogen. The mixture was stirred 7h at room temperature under an atmosphere of hydrogen (maintained with 2 atm pressure). The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 21.2 g (86%) of (1R,3s,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9- carboxylate and (1R,3r,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate as a white solid. 1H NMR (400 MHz, CDCl3) G : 4.55-4.21(m, 2H), 3.66-3.58(m, 0.27H), 2.73-2.62(m, 0.73H), 2.31-2.18(m, 1H), 2.01-1.89(m, 1H), 1.89-1.75(m, 3H), 1.70-1.52 (m, 3H), 1.52-1.49(m, 1H), 1.46(s, 9H), 1.45-1.35(m, 1.5H), 1.21-1.09(m, 1.5H) ppm. LCMS (Method D, ESI): RT=1.28 min, m/z =282.0 [M+H+CH3CN]+.
Step 3: Synthesis of (1R,3s,5S)-tert-butyl 3-(5-cyclopropylisoxazole-3- carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate and (1R,3r,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate
Figure imgf000275_0001
[0287] Into a 1000-mL round-bottom flask was placed (1R,3s,5S)-tert-butyl 3-amino-9- azabicyclo[3.3.1]nonane-9-carboxylate and (1R,3r,5S)-tert-butyl 3-amino-9- azabicyclo[3.3.1]nonane-9-carboxylate (20.5 g, 84.94 mmol, 1.00 equiv), dichloromethane (410 mL), 5-cyclopropyl-1,2-oxazole-3-carboxylic acid (19.6 g, 127.99 mmol, 1.51 equiv), EDCI (32.6 g, 170.06 mmol, 2.00 equiv), HOBT (17.3 g, 128.03 mmol, 1.51 equiv), TEA (43.1 g, 425.93 mmol, 5.01 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 400 mL of DCM. The resulting mixture was washed with 2x400 mL of H2O. The residue was purified on a silica gel column with dichloromethane/methanol (20:1). This resulted in 30.3 g (95%) of (1R,3s,5S)-tert-butyl 3-(5-cyclopropylisoxazole-3-carboxamido)-9- azabicyclo[3.3.1]nonane-9-carboxylate and (1R,3r,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate as a white solid. 1H NMR (300 MHz, CD3OD) G : 6.40(d, 1H), 5.01-4.90(m, 0.33H), 4.55- 4.29(m, 2H), 3.92-3.78(m, 0.67H), 2.37-2.21(m, 1.4H), 2.21-1.99(m, 2.6H), 1.95-1.70 (m, 2H), 1.68-1.54(m, 5H), 1.50(s, 9H),1.20-1.10(m, 2H), 1.01-0.91(m, 2H) ppm. LCMS (Method D, ESI): RT=2.22 min, m/z =361.0 [M-15+H]+.
Step 4: Synthesis of (1R,3s,5S)-tert-butyl 3-(5-cyclopropylisoxazole-3- carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate and (1R,3r,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate
Figure imgf000275_0002
[0288] The mixture of diastereomers (30g) was purified by prep-SFC with the following conditions: Column: Phenomenex Lux 5u Cellulose-35*25cm,5umChiral-P(Lux- 3)001608862-1; Detector: UV 220nm; Mobile Phase: CO2(70%), MeOH(30%). The resulting solution was concentrated under vacuum. This resulted in 20.6 g (95%) of (1R,3r,5S)-tert-butyl 3-(5-cyclopropylisoxazole-3-carboxamido)-9- azabicyclo[3.3.1]nonane-9-carboxylate as a white solid. 1H NMR (300 MHz, CD3OD) G : 6.35(s, 1H), 4.47(d, 2H), 3.90-3.75(m, 1 H), 2.35-2.23(m, 2H), 2.21-2.02(m, 2H),1.69- 1.52(m, 7H), 1.50 (s, 9H), 1.18-1.10(m, 2H), 0.98-0.90(m, 2H) ppm. LCMS (Method D, ESI): RT=2.20 min, m/z =320.0 [M-56+H]+. And 8.0 g (86%) of (1R,3s,5S)-tert-butyl 3- (5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate as a white solid. 1H NMR (300 MHz, CD3OD) G : 6.36(s, 1H), 5.02-4.91(m, 1H), 4.34(s, 2H), 2.22-2.10(m, 1H), 2.09-1.97(m, 3H), 1.93-1.64(m, 7H), 1.48 (s, 9H), 1.18-1.10(m, 2H), 0.98-0.90(m, 2H) ppm. LCMS (Method D, ESI): RT=2.19 min, m/z =320.0 [M-56+H]+.
Step 5: Synthesis of N-((1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5- cyclopropylisoxazole-3-carboxamide
Figure imgf000276_0001
[0289] Into a 250-mL round-bottom flask was placed (1R,3r,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate (20.6 g, 54.72 mmol, 1.00 equiv) anddichloromethane (150 mL). To the above hydrogen chloride was introduced. The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 400 mL of H2O. The pH value of the solution was adjusted to 9 with potassium carbonate. The resulting solution was extracted with 3x250 mL of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 14.2 g (94%) of N-((1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5- cyclopropylisoxazole-3-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD) G : 6.38(s, 1H), 4.29-4.20(m, 1H), 3.36(d, 2H), 2.28-2.11(m, 3H), 2.10-2.00(m, 1H), 1.79- 1.69(m, 2H), 1.58-1.37 (m, 5H), 1.19-1.11(m, 2H), 0.98-0.92(m, 2H) ppm. LCMS (Method D, ESI): RT=1.23 min, m/z =317.0 [M+H+CH3CN]+.
Step 6: Synthesis of N-((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5- cyclopropylisoxazole-3-carboxamide
Figure imgf000276_0002
[0290] Into a 250-mL round-bottom flask was placed (1R,3s,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate (8.0 g, 21.25 mmol, 1.00 equiv), dichloromethane (100 mL). To the above hydrogen chloride was introduced. The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 300 mL of H2O. The pH value of the solution was adjusted to 9 with potassium carbonate. The resulting solution was extracted with 3x100 mL of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 5.5 g (94%) of N-((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5- cyclopropylisoxazole-3-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD) G : 6.38(s, 1H), 4.89-4.80(m, 1H), 3.22(s, 2H), 2.21-2.13(m, 1H), 2.09-1.88(m, 5H),1.85- 1.70(m, 5H), 1.19-1.11(m, 2H), 0.98-0.92(m, 2H) ppm. LCMS (Method D, ESI): RT=1.20 min, m/z =276.0 [M+H]+. EXAMPLE 6
Synthesis of N-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3- carboxamide h drochloride
Figure imgf000277_0001
N-((1R,3s,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide h drochloride
Figure imgf000277_0002
Step 1: Synthesis of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000277_0003
[0291] Into a 2000-mL 3-necked round-bottom flask was placed HCOONH4 (42 g, 666.03 mmol, 30.00 equiv), acetic acid (1.3 g, 21.65 mmol, 1.00 equiv) and methanol (1.5 L). Then NaBH3CN (2.8 g, 44.56mmol, 2.00 equiv) was added into batch wise. This was followed by the addition of a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane- 8-carboxylate (5 g, 22.19mmol, 1.00 equiv) in methanol (100mL) dropwise with stirring at 25oC. The resulting solution was stirred for 12 h at 25oC. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200mL of H2O. The resulting solution was extracted with 3x200mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x200mL of brine (sat.). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with dichloromethane/methanol (9:1). This resulted in 4.8 g (90%) of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate as colorless oil. LCMS (method D, ESI): RT=0.97 min, m/z =227.0 [M+H]+.
Step 2: Synthesis of tert-butyl (1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3- amido)-8-azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,3s,5S)-3-(5- cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000278_0001
[0292] Into a 250-mL round-bottom flask was placed tert-butyl 3-amino-8- azabicyclo[3.2.1]octane-8-carboxylate (4 g, 17.67mmol, 1.00 equiv), 5-cyclopropyl-1,2- oxazole-3-carboxylic acid (2.7 g, 17.63mmol, 1.00 equiv), HATU (10 g, 26.30mmol, 1.50 equiv), DIEA (5.7 g, 44.10mmol, 2.50 equiv), DMF(100mL). The resulting solution was stirred for 12 h at 25oC. The reaction was then quenched by the addition of 100mL of water. The resulting solution was extracted with 3x100mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x100mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:4). The product (4.0g) was further purified by Prep-SFC with the following conditions (prep SFC 350): Column, Phenomenex Lux 5u Cellulose-3, 5*25cm, 5um; mobile phase, CO2(80%), methanol(20%); Detector, UV220nm. This resulted in 800 mg (13%) of tert- butyl (1R,3s,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8- carboxylate as a yellow solid. 1H NMR (400 MHz, CDCl3) G: 6.53 (d, J=8.0Hz, 1H), 6.33(s, 1H), 4.41-4.58(m, 1H), 4.24-4.32(m, 2H), 1.95-2.11 (m, 5H), 1.80-1.84(m, 2H), 1.57-1.63(m, 2H), 1.50(s, 9H), 1.16-1.28(m, 2H), 0.95-1.06(m, 2H)ppm. LCMS (method D, ESI): RT=2.33 min, m/z =362.0 [M+H]+ and 1.4 g (22%) of tert-butyl (1R,3r,5S)-3-(5- cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. 1H NMR (400 MHz, CDCl3) G: 7.21-7.23(d, J=7.6Hz, 1H), 6.34(s, 1H), 4.27- 4.33(m, 3H), 2.25-2.31(m, 2H), 2.07-2.14 (m, 3H), 1.91-1.95(m, 2H), 1.76-1.80(m, 2H), 1.49(s, 9H), 1.16-1.28(m, 2H), 0.95-1.06(m, 2H)ppm. LCMS (method D, ESI): RT=2.43 min, m/z =362.0 [M+H]+.
Step 3: Sytnthesis of N-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide hydrochloride and N-((1R,3s,5S)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride
Figure imgf000279_0001
[0293] Into two 50-mL round-bottom flasks was separately placed tert-butyl (1R,3r,5S)- 3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.66mmol, 1.00 equiv) and tert-butyl (1R,3s,5S)-3-(5-cyclopropyl-1,2-oxazole-3- amido)-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.66mmol, 1.00 equiv). This was followed by the addition of 10 mL of 1,4-dioxane into each flask. Then hydrogen chloride was introduced into the two mixtures. The resulting solutions were stirred for 2 h at 25oC. The resulting mixtures were concentrated under vacuum. This resulted in 480 mg (97%) of N-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3- carboxamide hydrochloride LCMS (method D, ESI): RT=0.97 min, m/z =262.0 [M+H]+ and 480 mg (97%) of N-((1R,3s,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide hydrochloride as a light yellow solid. LCMS (method D, ESI): RT=0.95 min, m/z =262.0 [M+H]+. EXAMPLE 7 Synthesis of N-[1-[(2S)-3-amino-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl] propanoyl]piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride salt
(Cpd. No. 121)
Figure imgf000280_0001
Step 1: Synthesis of ethyl (2E)-2-cyano-3-(4-hydroxyphenyl)prop-2-enoate
Figure imgf000280_0002
[0294] Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-hydroxybenzaldehyde (6 g, 49.13 mmol, 1.00 equiv) and ethanol (200 mL). Then ethyl 2-cyanoacetate (6.7 g, 59.23 mmol, 1.21 equiv) and piperidine (2 mL) was added. The resulting solution was stirred overnight at 90oC. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 8.5 g (80%) of ethyl (2E)-2-cyano-3-(4-hydroxyphenyl)prop-2-enoate as a yellow solid. 1H-NMR (300 MHz, CDCl3): į 8.19(s, 1H), 7.97(d, J=8.7 Hz, 2H), 6.99(d, J=8.7 Hz, 2H), 6.11 (brs, 1H), 4.41-4.31(m, 2H), 1.40(t, J=7.2 Hz, 3H) ppm. LCMS (method A, ESI): RT=1.34min, m/z =217.9 [M+H]+.
Step 2: Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[(4- hydroxyphenyl)methyl] propanoate
Figure imgf000281_0001
[0295] Into a 500-mL round-bottom flask was placed ethyl (2E)-2-cyano-3-(4- hydroxyphenyl)prop-2-enoate (8.5 g, 39.13 mmol, 1.00 equiv), methanol (200 mL) and di-tert-butyl dicarbonate (9.4 g, 43.07 mmol, 1.10 equiv). Then Raney-Ni (3 g) was added batchwise. Then H2 was introduced into mixture and maintained at 2 atm pressure. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 12 g (95%) of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxyphenyl)methyl]propanoate as a light yellow solid. LCMS (method C, ESI): RT=0.95 min, m/z =324.2 [M+H]+.
Step 3: Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxy-3- iodophenyl)methyl]propanoate
Figure imgf000281_0002
[0296] Into a 250-mL round-bottom flask was placed ethyl 3-[[(tert- butoxy)carbonyl]amino]-2-[(4-hydroxyphenyl)methyl]propanoate (5 g, 15.46 mmol, 1.00 equiv), TsOH (266 mg, 1.54 mmol, 0.10 equiv) and dichloromethane (80 mL). Then NIS (3.48 g, 15.47 mmol, 1.00 equiv) was added into at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 4.2 g (60%) of ethyl 3-[[(tert- butoxy)carbonyl]amino]-2-[(4-hydroxy-3-iodophenyl)methyl]propanoate as a light yellow solid. 1H-NMR (300 MHz, CDCl3): į 7.46(d, J=2.1 Hz, 1H), 7.06-7.02(m, 1H), 6.89(d, J=9.6 Hz, 1H), 4.15-4.07(m, 2H), 3.32-3.24(m, 2H), 2.84-2.72(m, 3H), 1.43(s, 9H), 1.19(t, J=6.9 Hz, 3H) ppm. LCMS (method A, ESI): RT=1.70 min, m/z =349.9 [M- Boc+H]+.
Step 4: Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3- (prop-1-en-2-yl)phenyl]methyl]propanoate
Figure imgf000282_0001
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxy-3- iodophenyl)methyl]propanoate (4 g, 8.90 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(prop- 1-en-2-yl)-1,3,2-dioxaborolane (1.8 g, 10.71 mmol, 1.20 equiv), Pd(dppf)Cl2 (650 mg), Cs2CO3 (8.7 g, 26.62 mmol, 2.99 equiv), and N,N-dimethylformamide (50 mL). The resulting solution was stirred overnight at 100oC. The resulting solution was diluted with 40 mL of NH4Cl (sat. aq.). The resulting solution was extracted with 4x40 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4x50 mL of NH4Cl (sat. aq.). The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 1 g (31%) of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(prop-1- en-2-yl)phenyl]methyl]propanoate as light brown oil. LCMS (method A, ESI): RT=1.74 min, m/z =264.0 [M-Boc+H]+.
Step 5: Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3- (propan-yl)phenyl]methyl]propanoate
Figure imgf000282_0002
[0297] Into a 250-mL round-bottom flask, was placed ethyl 3-[[(tert- butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(prop-1-en-2-yl)phenyl]methyl]propanoate (1.3 g, 3.58 mmol, 1.00 equiv), ethyl acetate (40 mL) and 10% Palladium carbon (0.7 g). Then H2 was introduced into mixture and maintained at 2 atm pressure. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.0 g (76%) of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan-2- yl)phenyl]methyl]propanoate as light yellow oil. LCMS (method D, ESI): RT=1.57 min, m/z =366.0 [M+H]+.
Step 6: Synthesis of 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan- 2-yl)phenyl]methyl]propanoic acid
Figure imgf000283_0001
[0298] Into a 250-mL round-bottom flask was placed ethyl 3-[[(tert- butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]propanoate (1 g, 2.74 mmol, 1.00 equiv), ethanol (40 mL), water(0.5 mL), sodium hydroxide (0.45 g). The resulting solution was stirred for 6 h at room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 4 with hydrochloric acid (12N). The resulting solution was extracted with 5x30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 0.6 g (65%) of 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan-2- yl)phenyl]methyl]propanoic acid as colorless oil. LCMS (method A, ESI): RT=1.56 min, m/z =360.1 [M+Na]+.
Step 7: Synthesis of tert-butyl N-[3-[4-(5-cyclopropyl-1,2-oxazole-3- amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3- oxopropyl]carbamate
Figure imgf000284_0001
[0299] Into a 250-mL round-bottom flask was placed 3-[[(tert-butoxy)carbonyl]amino]- 2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]propanoic acid (600 mg, 1.78 mmol, 1.00 equiv), 5-cyclopropyl-N-(piperidin-4-yl)-1,2-oxazole-3-carboxamide hydrochloride (750 mg, 2.76 mmol, 1.55 equiv), EDCI (0.85 g), HOBT (0.6 g) and dichloromethane (60 mL). Then TEA (0.9 g) was added into dropwise at 0oC. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:10). The product was further purified by Prep-HPLC with the following conditions (2#-Waters 2767-2(HPLC-08)): Column, Xbridge Prep Phenyl, 5 um, 19x150 mm; mobile phase, Water with 50 mmol ammonium bicarbonate and acetonitrile (10.0% acetonitrile up to 33.0% in 2 min, up to 53.0% in 8 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm. This resulted in 650 mg (66%) of tert-butyl N-[3- [4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2- yl)phenyl]methyl]-3-oxopropyl]carbamate as a white solid. LCMS (method A, ESI): RT=1.69 min, m/z =455.2 [M-Boc +H]+.
Step 8: Synthesis of tert-butyl N-[(2S)-3-[4-(5-cyclopropyl-1,2-oxazole-3- amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3- oxopropyl]carbamate
Figure imgf000284_0002
[0300] The tert-butyl N-[3-[4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-[[4- hydroxy-3-(propan-2-yl)phenyl]methyl]-3-oxopropyl]carbamate (600 mg, 1.08 mmol, 1.00 equiv) was separated by Chiral-HPLC with following conditions: (Chiral-p(Lux- 4)003667995-2): Column, Phenomenex Lux 5u Cellulose-4 AXIA Packed250*21.2 mm,5 um, mobile phase, Phase A: Hex-HPLC and Phase B: EtOH-HPLC Gradient; Detector, uv 254/220 nm. This resulted in 256 mg (43%) of tert-butyl N-[(2S)-3-[4-(5- cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2- yl)phenyl]methyl]-3-oxopropyl]carbamate as a white solid. LCMS (method A, ESI): RT=1.68 min, m/z =455.3 [M-Boc +H]+.
Step 9: Synthesis of N-[1-[(2S)-3-Amino-2-[[4-hydroxy-3-(propan-2- yl)phenyl]methyl] propanoyl]piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride salt
Figure imgf000285_0001
[0301] Into a 100-mL round-bottom flask was placed tert-butyl N-[(2S)-3-[4-(5- cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2- yl)phenyl]methyl]-3-oxopropyl]carbamate (256 mg, 0.46 mmol, 1.00 equiv) and dichloromethane (20 mL). Then hydrogen chloride was introduced into mixture. The resulting solution was stirred for 4 h at room temperature. The solids were collected by filtration. The resulting filtrate was concentrated under vacuum. This resulted in 152.2 mg (67%) of N-[1-[(2S)-3-amino-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl] propanoyl]piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride as a white solid. 1H-NMR (300 MHz, CD3OD): į 6.99(dd, J=20.4 and 2.1 Hz, 1H), 6.86- 6.81(m, 1H), 6.73-6.69(m, 1H), 6.36(d, J=0.6 Hz, 1H), 4.60-4.37(m, 1H), 4.05-3.88(m, 1H), 3.87-3.63(m, 1H), 3.50-3.36(m, 1H), 3.30-2.98(m, 3.5H), 2.88-2.72(m, 3H), 2.62- 2.45(m, 0.5H), 2.21-2.11(m, 1H), 1.96-1.62(m, 2H), 1.62-1.42(m, 1H), 1.40-1.24(m, 0.5H), 1.23-1.18(m, 6H), 1.18-1.09(m, 2H), 1.02-0.90(m, 2H), 0.78-0.60(m, 0.5H) ppm. LCMS (method D, ESI): RT=1.96 min, m/z =455.1 [M+H]+. ee=100%. EXAMPLE 8
Synthesis of N-((2R,4S,5R)-1-((1r,4R)-4-aminocyclohexanecarbonyl)-2,5- dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide (Cpd. No. 420)
Figure imgf000286_0001
Step 1: Synthesis of tert-butyl 2,5-dimethylpyridin-4-ylcarbamate
Figure imgf000286_0002
[0302] Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2,5-dimethylpyridin-4-amine (488 mg, 3.99 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), di-tert-butyl dicarbonate (959.2 mg, 4.40 mmol, 1.10 equiv). This was followed by the addition of LiHMDS ((7.98mL, 7.98 mmol, 2.00 equiv, 1M in THF solution) dropwise with stirring at 0oC. The resulting solution was stirred at 25oC overnight. The reaction was then quenched by the addition of 50 mL of NH4Cl (sat. aq.). The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane/methanol (100:1). This resulted in 740 mg (83%) of tert-butyl 2,5- dimethylpyridin-4-ylcarbamate as yellow oil. LCMS (method C, ESI): RT=0.83min, m/z=223.0 [M+H]+.
Step 2: Synthesis of tert-butyl 2,5-dimethylpiperidin-4-ylcarbamate
Figure imgf000286_0003
[0303] Into a 30-mL high pressure tank reactor (70 atm), was placed a solution of tert- butyl N-(2,5-dimethylpyridin-4-yl)carbamate (1.11 g, 4.99 mmol, 1.00 equiv) in ethanol (25 mL), and 5% Rh/Al2O3. Then hydrogen was introduced into mixture and maintained at 70 atm. The resulting solution was stirred for 2 days at 70oC. The reaction mixture was cooled to 25oC. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 440 mg of tert-butyl 2,5-dimethylpiperidin-4-ylcarbamate as black oil. LCMS (method A, ESI): RT=1.12min, m/z=229.0 [M+H]+.
Step 3: Synthesis of tert-butyl 1-((1R,4R)-4-(1,3-dioxoisoindolin-2- yl)cyclohexanecarbonyl) -2,5-dimethylpiperidin-4-ylcarbamate
Figure imgf000287_0001
[0304] Into a 25-mL round-bottom flask was placed tert-butyl N-(2,5-dimethylpiperidin- 4-yl)carbamate (183.7 mg, 0.80 mmol, 1.10 equiv), (1R,4R)-4-(1,3-dioxo-2,3-dihydro- 1H-isoindol-2-yl)cyclohexane-1-carboxylic acid (200 mg, 0.73 mmol, 1.00 equiv), HATU (334 mg, 0.88 mmol, 1.20 equiv). This was followed by the addition of TEA (370 mg, 3.66 mmol, 5.00 equiv) by dropwise with stirring. The resulting solution was stirred for 16 hours at 25oC. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 3x30 mL of brine (sat. aq.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane/methanol (100:1). This resulted in 700 mg of tert-butyl 1-((1R,4R)-4-(1,3-dioxoisoindolin-2-yl)cyclohexanecarbonyl)-2,5- dimethylpiperidin-4-ylcarbamate as yellow oil. LCMS (method D, ESI): RT=0.91min, m/z=484.0 [M+H]+.
Step 4: Synthesis of 2-((1R,4R)-4-(4-Amino-2,5-dimethylpiperidine-1- carbonyl)cyclohexyl) isoindoline-1,3-dione h drochloride
Figure imgf000287_0002
[0305] Into a 100-mL round-bottom flask was placed a solution of tert-butyl N-(2,5- dimethyl-1-[[(1R,4R)-4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2- yl)cyclohexyl]carbonyl]piperidin-4-yl)carbamate (700 mg, 1.45 mmol, 1.00 equiv) in dichloromethane (30 mL). To the above hydrogen chloride was introduced. The resulting solution was stirred for 30 min at 25oC. The resulting mixture was concentrated under vacuum. This resulted in 490 mg of 2-((1R,4R)-4-(4-amino-2,5-dimethylpiperidine-1- carbonyl)cyclohexyl)isoindoline-1,3-dione hydrochloride as yellow oil. LCMS (method C, ESI): RT=1.11 min, m/z=384.0[M+H]+.
Step 5: Synthesis of 5-Cyclopropyl-N-(1-((1R,4R)-4-(1,3-dioxoisoindolin-2- yl)cyclohexanecarbonyl)-2,5-dimethylpiperidin-4-yl)isoxazole-3-carboxamide
Figure imgf000288_0001
[0306] Into a 100-mL round-bottom flask was placed 2-[(1R,4R)-4-[(4-amino-2,5- dimethylpiperidin-1-yl)carbonyl]cyclohexyl]-2,3-dihydro-1H-isoindole-1,3-dione (838 mg, 2.19 mmol, 1.10 equiv), 5-cyclopropyl-1,2-oxazole-3-carboxylic acid (306 mg, 2.00 mmol, 1.00 equiv), HATU (912 mg, 2.40 mmol, 1.20 equiv). This was followed by the addition of triethylamine (1 g, 9.88 mmol, 5.00 equiv) dropwise with stirring. The resulting solution was stirred at 25oC overnight. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 3x30 mL of brine (sat.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane/methanol (100:1). This resulted in 500 mg of 5-cyclopropyl-N-(2,5-dimethyl-1-[[(1R,4R)-4-(1,3- dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclohexyl]carbonyl]piperidin-4-yl)-1,2-oxazole-3- carboxamide as yellow oil. LCMS (method C, ESI): RT=0.99 min, m/z=519.0[M+H]+ Step 6: Synthesis of N-(1-((1R,4R)-4-Aminocyclohexanecarbonyl)-2,5- dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000288_0002
[0307] Into a 100-mL round-bottom flask was placed 5-cyclopropyl-N-(2,5-dimethyl-1- [[(1R,4R)-4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclohexyl]carbonyl]piperidin-4- yl)-1,2-oxazole-3-carboxamide (518 mg, 1.00 mmol, 1.00 equiv), water (1 mL) and propan-2-ol (6 mL). Then NaBH4 (380 mg, 10.05 mmol, 10.00 equiv) was added batchwise. The resulting solution was stirred for 16 hours at 25oC. This was followed by the addition of acetic acid (0.2 mL, 0.10 equiv) dropwise with stirring. The resulting solution was allowed to react with stirring for 2 hour while the temperature was maintained at 80oC in an oil bath. Then the reaction system was cooled. The pH value of the solution was adjusted to 8 with sodium carbonate (50 %, aq.). The resulting solution was extracted with 3x15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane/methanol (100:1). This resulted in 72.9 mg (19%) of 5-cyclopropyl-N-(2,5-dimethyl-1-[[(1R,4R)-4- aminocyclohexyl]carbonyl]piperidin-4-yl)-1,2-oxazole-3-carboxamide as a white solid. 1H-NMR (400 MHz, CD3OD): į 6.40(s, 1 H), 4.89-3.70 (m, 3 H), 3.32-2.68(m, 3H), 2.27-2.09(m, 4 H), 1.95-1.90 (m, 4 H), 1.68-1.47(m, 4 H), 1.34-1.11(m, 5 H), 0.92- 1.01(m, 5 H) ppm. LCMS (method A, ESI): RT=1.32 min, m/z=389.0[M+H]+.
Step 7: Synthesis of N-((2R,4S,5R)-1-((1r,4R)-4-Aminocyclohexanecarbonyl)- 2,5-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000289_0001
[0308] The crude product was purified by Chrial-HPLC with the following conditions:
Column, SHIMADZU-PDA(LC-08) ; mobile phase, Hex ( 0.2%IPA) : EtOH=70:30; Detector, UV 254/220 nm. This resulted in 9.6 mg (24%) of (2S,4R,5S)-benzyl 4-(5- cyclopropylisoxazole-3-carboxamido)-2,5-dimethylpiperidine-1-carboxylate as a white solid and 9.3 mg (23%) of (2R,4S,5R)-benzyl 4-(5-cyclopropylisoxazole-3- carboxamido)-2,5-dimethylpiperidine-1-carboxylate was obtained as a white solid. 1H- NMR (400 MHz, CD3OD): į 6.30(s, 1 H), 4.76-3.60 (m, 3 H), 3.10-2.90(m, 1 H), 2.85- 2.75(m, 1 H), 2.61-2.45(m, 1H), 2.10-2.03(m, 2 H), 1.93-1.73 (m, 6 H), 1.57-1.31(m, 2 H), 1.31-1.02(m, 7 H), 0.89-0.84(m, 5 H) ppm. LCMS (method A, ESI): RT=1.31 min, m/z=389.0[M+H]+. EXAMPLE 9
Synthesis of N-((3S,4R)-1-(3-aminopropylsulfonyl)-3-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide (Cpd. No. 386)
Figure imgf000289_0002
Step 1: Synthesis of tert-butyl 4-amino-3-methylpiperidine-1-carboxylate
Figure imgf000290_0001
[0309] Into a 4-L round-bottom flask was placed methanol (3 L), formic acid (0.5 mL), HCOONH4 (84 g, 1.33 mol, 40.00 equiv) and tert-butyl 3-methyl-4-oxopiperidine-1- carboxylate (7 g, 32.82 mmol, 1.00 equiv).Then NaBH3CN (4.1 g, 2.00 equiv) was added into batchwise. The resulting solution was stirred for 2 hours at room temperature. The pH value of the solution was adjusted to 9 with sodium carbonate (5M in water). The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H2O. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. This resulted in 7.0 g (99% crude) of tert-butyl 4- amino-3-methylpiperidine-1-carboxylate as a white solid. 1H NMR (300 MHz, DMSO): 6.39(brs, 2H), 3.95-3.75(m, 1.5H), 3.70-3.60(m, 0.5H), 3.35-3.25(brs, 0.5H), 3.05- 2.95(m, 0.5H), 2.90-2.63(m, 1.5H), 2.45-2.25(brs, 0.5H), 2.10-2.00 (brs, 0.5H), 1.95- 1.85(m, 0.5H), 1.65-1.45(m, 1.5H), 1.35-1.25(m, 0.5H), 1.38(s, 9H), 1.20-1.10(m, 3H) ppm. LCMS (Method A, ESI): RT=1.02 min, m/z =215.0 [M+H]+.
Step 2: Synthesis of tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-3- methylpiperidine-1-carboxylate
Figure imgf000290_0002
[0310] Into a 250-mL round-bottom flask was placed tert-butyl 4-amino-3- methylpiperidine-1-carboxylate (7 g, 32.66 mmol, 1.00 equiv), dichloromethane (100 mL), 5-cyclopropyl-1,2-oxazole-3-carboxylic acid (6.5 g, 42.45 mmol, 1.30 equiv), HATU (25.1 g, 104.13 mmol, 2.00 equiv). Then TEA (16.7 g, 165.04 mmol, 5.00 equiv) was added into mixture dropwise. The resulting solution was stirred for 2 h at room temperature. The resulting solution was concentrated under vacuum. The resulting solution was diluted with 50 mL of H2O. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x150 mL of brine (sat.). The mixture was dried over anhydrous sodium sulfate. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 6 g (52%) of tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-3- methylpiperidine-1-carboxylateas yellow solid. 1H NMR (400 MHz, CD3OD) : 6.38(s, 1H), 4.30-4.20(m, 1H), 4.20-4.05(m, 1H), 3.80-3.76(m, 1H), 3.56-3.45 (m, 1H), 3.29- 3.20 (m, 1H), 2.15-2.10(m, 2H), 1.90-1.80(m, 1H), 1.70-1.60(m, 1H), 1.52(s, 9H), 1.20- 1.16(m, 2H), 1.05-0.85(m, 5H) ppm. LCMS (Method A, ESI): RT=1.47 min, m/z =294.0 [M+H-56]+.
Step 3: Synthesis of (3S,4R)-tert-butyl 4-(5-cyclopropylisoxazole-3- carboxamido)-3-methylpi eridine-1-carbox late
Figure imgf000291_0001
[0311] 1.5g of tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-3-methylpiperidine- 1-carboxylatewas purified by Chrial-Prep-SFC with the following conditions: Column: CHIRALCEL OJ-3 (0.46*15cm,3um); mobile phase, Hex:EtOH=90:10; Detector, 254nm. This resulted in 240 mg (16%) of (3S,4R)-tert-butyl 4-(5-cyclopropylisoxazole- 3-carboxamido)-3-methylpiperidine-1-carboxylateas a white solid. 1H NMR (400 MHz, CD3OD) : 6.40(s, 1H), 4.25-4.22(m, 1H), 4.00-3.88(brs, 1H), 3.77-3.55(brs, 1H), 3.24- 3.23(m, 2H), 2.20-2.15 (m, 2H), 1.85-1.81(m, 1H), 1.67-1.64(m, 1H) , 1.48(s, 9H) 1.17- 1.16(m, 2H), 1.05-0.98(m, 5H) ppm.
Step 4: Synthesis of 5-cyclopropyl-N-((3S,4R)-3-methylpiperidin-4-yl)isoxazole- 3-carboxamide
Figure imgf000291_0002
[0312] Into a 100-mL round-bottom flask was placed (3S,4R)-tert-butyl 4-(5- cyclopropylisoxazole-3-carboxamido)-3-methylpiperidine-1-carboxylate (240 mg, 0.688 mmol, 1.00 equiv), dichloromethane (30 mL). To the above hydrogen chloride was introduced. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The pH value of the solution was adjusted to 9 with sodium carbonate (5M in water). The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined. This resulted in 150 mg (71%) of 5-cyclopropyl-N-[(3S,4R)-3- methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD) : 6.40(s, 1H), 4.28-4.26(m, 1H), 3.05-2.90(brs, 1H), 2.90-2.70(m, 3H), 2.20- 2.05 (m, 2H), 1.90-1.70(m, 2H), 1.20-1.10(m, 2H) , 1.05-0.95(m, 5H) ppm. LCMS (Method A, ESI): RT=0.97 min, m/z =250.0 [M+H].
Step 5: Synthesis of 5-cyclopropyl-N-((3S,4R)-1-(3-(1,3-dioxoisoindolin-2- yl)propylsulfonyl)-3-meth l i eridin-4- l isoxazole-3-carboxamide
Figure imgf000292_0001
[0313] Into a 25-mL round-bottom flask was placed 5-cyclopropyl-N-((3S,4R)-3- methylpiperidin-4-yl)isoxazole-3-carboxamide (150 mg, 0.60 mmol, 1.00 equiv), dichloromethane (20 mL) and TEA (180 mg, 3.00 equiv). Then 3-(1,3-dioxo-2,3- dihydro-1H-inden-2-yl)propane-1-sulfonyl chloride (207 mg, 0.72 mmol, 1.30 equiv) was added into the mixture dropwise at-20oC. The resulting solution was stirred for additional 24 hours at -20oC. The resulting mixture was concentrated under vacuum. The resulting mixture was triturated with 3x10 mL of EA. The solids were collected by filtration. This resulted in 300 mg (100%) of 5-cyclopropyl-N-[(3S,4R)-1-[[3-(1,3-dioxo- 2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-3-methylpiperidin-4-yl]-1,2-oxazole-3- carboxamide as a white solid. LCMS (method A, ESI): RT=1.40 min, m/z =501.0 [M+H].
Step 6: Synthesis of N-((3S,4R)-1-(3-aminopropylsulfonyl)-3-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000292_0002
[0314] Into a 25-mL round-bottom flask was placed 5-cyclopropyl-N-[(3S,4R)-1-[[3- (1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-3-methylpiperidin-4-yl]-1,2- oxazole-3-carboxamide (300 mg, 0.60 mmol, 1.00 equiv), methanol (10 mL) and hydrazine hydrate (1 mL, 80% in water). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions : Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A:Water/NH4HCO3 10mmol, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 30%B to 85%B in 10 min; Detector,254nm This resulted in 66.4 mg (30%) of N-[(3R,4S)-1-[(3- aminopropane)sulfonyl]-3-methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3- carboxamide as a white solid. 1H NMR (300 MHz, CD3OD) G : 6.40(s, 1H), 4.24- 4.20(m, 1H), 3.61-3.57(m, 1H), 3.50-3.32(m, 1H), 3.25-3.08(m, 4H), 2.85- 2.75 (m, 2H), 2.30-2.14(m, 2H), 2.00-1.89(m, 3H), 1.80-1.70(m, 1H), 1.20-1.15(m, 2H), 1.10-0.95(m, 5H) ppm. LCMS (Method D, ESI): RT=2.11 min, m/z =371.0 [M+H]+. EXAMPLE 10
Synthesis of N-[9-[(3-aminopropane)sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl]-5- cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride salt (Cpd. No.181
Figure imgf000293_0001
Step 1: Synthesis of 5-cyclopropyl-N-(9-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol- 2-yl)propane]sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl)-1,2-oxazole-3-carboxamide
Figure imgf000293_0002
[0315] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of argon was placed N-[9-azabicyclo[3.3.1]nonan-3-yl]-5-cyclopropyl-1,2- oxazole-3-carboxamide (250 mg, 0.91 mmol, 1.00 equiv), tetrahydrofuran (20 mL), the solution was cooled to -30oC, then LiHMDS (3 mL) was added and stirred for 30 min at - 30oC, and a solution of 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane-1-sulfonyl chloride (340 mg, 1.18 mmol, 1.30 equiv) in tetrahydrofuran (3 mL) was added slowly. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 10 mL of ethyl acetate. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 200 mg (42%) of 5-cyclopropyl- N-(9-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-9- azabicyclo[3.3.1]nonan-3-yl)-1,2-oxazole-3-carboxamide as a white solid.1H-NMR (400 MHz, CDCl3): į 8.50 (d, J=8.0 Hz, 1H), 7.89-7.82 (m, 4H), 6.47 (s, 1H), 4.78-4.77(m, 1H), 4.00-3.98(m, 2H), 3.70(t, J=7.2 Hz, 2H), 3.20(t, J=7.2 Hz, 2H), 2.20-2.16(m, 1H), 2.01-1.97(m, 2H), 1.87-1.81(m, 7H), 1.68(d, J=8.4 Hz, 3H), 1.13-1.06 (m, 2H), 0.93-0.89 (m, 2H) ppm. LCMS (method D, ESI): RT=1.48min, m/z =527.1 [M+H]+.
Step 2: Synthesis of N-[9-[(3-aminopropane)sulfonyl]-9-azabicyclo[3.3.1]nonan- 3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride salt
Figure imgf000294_0001
[0316] Into a 250-mL round-bottom flask, was placed 5-cyclopropyl-N-(9-[[3-(1,3- dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl)- 1,2-oxazole-3-carboxamide (200 mg, 0.38 mmol, 1.00 equiv), methanol (30 mL)and hydrazine hydrate (4 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate. The crude product (200 mg) was further purified by Prep-HPLC with the following conditions: Column, X Bridge C18, 19*150 mm, 5 um; mobile phase, Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 20 mL/min; Detector, 254 nm. This resulted in 118.7 mg (72%) of N-[9-[(3- aminopropane)sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl]-5-cyclopropyl-1,2-oxazole-3- carboxamide hydrochloride as a white solid. 1H-NMR (300 MHz, CD3OD): į 6.40 (s, 1H), 5.04-4.89 (m, 1H), 4.14 (brs, 2H), 3.24 (t, J=7.5 Hz, 2H), 3.13 (t, J=7.8 Hz, 2H), 2.20-1.77 (m, 13H), 1.17-1.12 (m, 2H), 0.99-0.94(m, 2H) ppm. LCMS (method D, ESI): RT=1.35 min, m/z =397.0 [M+H]+. EXAMPLE 11
Synthesis of 5-cyclopropyl-N-[(2S,4S)-2-methyl-1 -(4-methylpiperazine-1-sulfonyl) piperidin-4-yl]-1,2-oxazole-3-carboxamide (Cpd. No. 279)
Figure imgf000294_0002
[0317] Into a 50-mL 3-necked round-bottom flask was placed 5-cyclopropyl-N-((2S,4S)- 2-methylpiperidin-4-yl)isoxazole-3-carboxamide hydrochloride (200 mg, 0.70 mmol, 1.00 equiv), dichloromethane (10 mL) and TEA (353 mg, 3.49 mmol, 4.98 equiv). This was followed by the addition of 4-methylpiperazine-1-sulfonyl chloride (166 mg, 0.84 mmol, 1.19 equiv) at -20oC. The resulting solution was stirred at room temperature overnight. The reaction progress was monitored by LCMS. The resulting mixture was washed with 2x5 mL of H2O. The residue was purified on a silica gel column with dichloromethane/methanol (20:1). This resulted in 136.3 mg (47%) of 5-cyclopropyl-N- [(2S,4S)-2-methyl-1-(4-methylpiperazine-1-sulfonyl)piperidin-4-yl]-1,2-oxazole-3- carboxamide as a white solid. 1H NMR (300 MHz, CD3OD) G : 6.37(s, 1H), 4.14- 4.11(m, 1H), 3.76-3.63(m, 2H), 3.27-3.24(m, 1H), 3.21(t, 4H), 2.51(t, 4H), 2.32 (s, 3H), 2.19-2.13(m, 1H), 2.01-1.95(m, 2H), 1.85-1.65(m, 2H), 1.41(d, 3H), 1.17-1.10(m, 2H), 0.99-0.94(m, 2H) ppm. LCMS (Method D, ESI): RT=1.74 min, m/z =412.0 [M+H]+. EXAMPLE 12
Synthesis of N-((2S,4S)-2-benzyl-1-(2-(piperidin-4-yl)acetyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide h drochloride Cpd. No. 348)
Figure imgf000295_0001
Step 1: Synthesis of tert-butyl 4-[2-[(2S,4S)-2-benzyl-4-(5-cyclopropyl-1,2- oxazole-3-amido)pi eridin-1- l -2-oxoeth l i eridine-1-carbox late
Figure imgf000295_0002
[0318] Into a 250-mL round-bottom flask was placed N-[(2S,4S)-2-benzylpiperidin-4-yl]- 5-cyclopropyl-1,2-oxazole-3-carboxamide (100 mg, 0.31 mmol, 1.00 equiv), dichloromethane (50 mL), HATU (353 mg, 0.93 mmol, 3.02 equiv), TEA (157 mg, 1.55 mmol, 5.05 equiv), 2-[1-[(tert-butoxy)carbonyl]piperidin-4-yl]acetic acid (75 mg, 0.31 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 130 mg (77%) of tert-butyl 4-[2-[(2S,4S)-2-benzyl-4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]- 2-oxoethyl]piperidine-1-carboxylate as a yellow solid. LCMS (method A, ESI) : RT=1.13 min. m/z = 451.0 [M-Boc]+.
Step 2: Synthesis of N-((2S,4S)-2-benzyl-1-(2-(piperidin-4-yl)acetyl)piperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride
Figure imgf000296_0001
[0319] Into a 100-mL round-bottom flask was placed tert-butyl 4-[2-[(2S,4S)-2-benzyl-4- (5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxylate (130 mg, 0.24 mmol, 1.00 equiv) and 1,4-dioxane (20 mL). Then hydrogen chloride was introduced into mixture. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 64.0 mg (56%) of N-[(2S,4S)-2-benzyl-1-[2-(piperidin-4-yl)acetyl]piperidin-4-yl]-5- cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride as a white solid. 1H NMR (400 MHz, D2O): G : 7.22-7.06 (m, 5H), 6.30 (s, 1H ), 4.70 (s, 0.5H), 4.38-4.30 (m, 0.5H), 4.30-4.15 (m, 0.5H), 4.15-3.95 (m, 1H), 3.75-3.65(m, 0.5H), 3.65-3.45 (m, 0.5H), 3.30- 3.01 (m, 3H), 3.01-2.90 (m, 0.5H), 2.90-2.70 (m, 3H), 2.45-2.35 (m, 0.5H), 2.20-2.01 (m, 2H), 2.01-1.81 (m, 4H), 1.81-1.65 (m, 1.5H), 1.65-1.51 (m, 1H), 1.51-1.41 (m, 1H), 1.41- 1.39 ( m, 1.5H), 1.10-1.01 ( m, 2H), 0.98-0.83 (m, 2.5H) ppm. LCMS (method D, ESI): RT=1.98 min. m/z = 451.0 [M-HCl]+. EXAMPLE 13
Synthesis of N-((1S,3r,5R)-8-(3-aminopropylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide (Cpd. No. 485)
Figure imgf000297_0001
Step 1: Synthesis of N-((1R,3r,5S)-8-(3-chloropropylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000297_0002
[0320] Into a 25-mL round-bottom flask was placed N-[(1 R,3r,5S)-8- azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide (200 mg, 0.62mmol, 1.00 equiv), dichloromethane (5mL), TEA (189 mg, 1.87mmol, 3.00 equiv). This was followed by the added of 3-chloropropane-1-sulfonyl chloride (143 mg, 0.81mmol, 1.30 equiv) dropwise at 0oC. The resulting solution was stirred overnight at 25oC. The solution was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 240 mg (96%) of N- [(1R,3r5S)-8-[(3-chloropropane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl- 1,2-oxazole-3-carboxamide as yellow oil. LCMS (method D, ESI): RT=0.97min, m/z =402.0 [M+H]+.
Step 2: Synthesis of 5-cyclopropyl-N-((1S,3r,5R)-8-(3-(1,3-dioxoisoindolin-2- yl)propylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide
Figure imgf000297_0003
[0321] Into a 25-mL round-bottom flask was placed N-[(1R,3S,5S)-8-[(3- chloropropane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3- carboxamide (100 mg, 0.25mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), 2- potassio-2,3-dihydro-1H-isoindole-1,3-dione (92 mg, 0.50mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 80oC. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x70 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 120 mg (94%) of 5-cyclopropyl-N- [(1R,3r,5S)-8-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-8- azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide as a white solid. LCMS (method D, ESI): RT=0.98 min, m/z =513.0 [M+H]+.
Step 3: Synthesis of N-((1S,3r,5R)-8-(3-aminopropylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000298_0001
[0322] Into a 25-mL round-bottom flask was placed 5-cyclopropyl-N-[(1R,3r,5S)-8-[[3- (1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-8-azabicyclo[3.2.1]octan-3- yl]-1,2-oxazole-3-carboxamide (120 mg, 0.23mmol, 1.00 equiv) and N2H4.H2O (0.2 mL), methanol (7 mL). The resulting solution was stirred for 4 h at 25oC. The mixture was concentrated under vacuum and then dissolved in 50mL ethyl acetate. The solids were filtered out. The filtrate was concentrated under vacuum. The crude product (100mg) was purified by Prep-HPLC with the following conditions(1#-Waters 2767-1): Column, X- bridge Prep phenyl 5um,19*150mmh Prep C012(T)186003581138241113.01; mobile phase, Phase A:water with 0.5% NH4HCO3 ,Phase B:CH3CN .Water with 0.5% NH4HCO3 and CH3CN (30% CH3CN up to 60% in 12 min ,hold 95% in 1min ,down to 30% in 1 min); Detector, uv254nm. This resulted in 50.7 mg (57%) of N-[(1R,3r,5S)-8- [(3-aminopropane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3- carboxamide as a white solid. 1H NMR (400 MHz, CD3OD): 6.28 (s, 1H), 4.13 (s, 2H), 4.07-4.04 (m, 1H), 3.07-3.03 (m, 2H), 2.69-2.66 (m, 2H), 2.21-2.15(m, 2H), 2.08-1.80 (m, 9H), 1.06-1.01 (m, 2H), 0.89-0.85 (m, 2H) ppm. LCMS (method D, ESI): RT=1.30 min, m/z =383.0 [M+H]+. EXAMPLE 14
Synthesis of 5-cyclopropyl-N-((1R,3s,5S)-8-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide (Cpd. No. 436
Figure imgf000299_0001
Step 1: Synthesis of 5-cyclopropyl-N-((1R,3s,5S)-8-(vinylsulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide
Figure imgf000299_0003
[0323] Into a 50-mL round-bottom flask was placed N-[(1R,3s,5S)-8- azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1 ,2-oxazole-3-carboxamide hydrochloride (100 mg, 0.34 mmol, 1.00 equiv), TEA (102 mg, 1.01 mmol, 3.00 equiv), dichloromethane (5 mL). This was followed by the dropwise addition of ethenesulfonyl chloride (61 mg, 0.48 mmol, 1.30 equiv) at 0oC. Then the resulting solution was stirred for 2 h at 25oC. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (3:1). This resulted in 100 mg (85%) of 5-cyclopropyl-N-[(1R,3s,5S)-8-(ethenesulfonyl)-8- azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide as a light brown solid. LCMS (method D, ESI): RT=0.59 min, m/z =383.1 [M+Na]+.
Step 2: Synthesis of 5-cyclopropyl-N-((1R,3s,5S)-8-((2-(pyrrolidin-1- yl)ethyl)sulfonyl)-8-azabicyclo 3.2.1 octan-3- l isoxazole-3-carboxamide
Figure imgf000299_0002
[0324] Into a 50-mL round-bottom flask was placed 5-cyclopropyl-N-[(1R,3s,5S)-8- (ethenesulfonyl)-8-azabicyclo[3.2.1 ]octan-3-yl]-1,2-oxazole-3-carboxamide (90 mg, 0.26mmol, 1.00 equiv), ethanol (10 mL), and pyrrolidine (0.2 mL). The resulting solution was stirred at 25oC overnight. The resulting mixture was concentrated under vacuum. The crude product (89mg) was purified by Prep-HPLC with the following conditions(1#- Waters 2767-1): Column, X-bridge Prep phenyl 5um,19*150mmh Prep C012(T)186003581138241113.01; mobile phase, Phase A:water with 0.5% NH4HCO3 ,Phase B:CH3CN .Water with 0.5% NH4HCO3 and CH3CN (80% CH3CN up to 95% in 13 min ,hold 95% in 1min ,down to 80% in 1 min); Detector, uv254nm. This resulted in 60.3 mg (56%) of 5-cyclopropyl-N-[(1R,3s,5S)-8-[[2-(pyrrolidin-1-yl)ethane]sulfonyl]-8- azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide as a white solid. 1H-NMR (400 MHz, CD3OD): į6.27 (s, 1H), 4.21-4.11 (m, 2H), 4.02-4.08 (m, 1H), 3.22-3.18 (m, 2H), 2.84-2.79 (m, 2H), 2.52-2.49 (m, 4H), 2.19-2.14 (m, 2H), 2.08-1.72 (m, 11H), 1.06-1.01 (m, 2H), 0.89-0.85 (m, 2H) ppm. LCMS (method D, ESI): RT=1.36 min, m/z =423 [M+H]+. EXAMPLE 15
Synthesis of N-((2S,4S)-1-(3-(benzylamino)propylsulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide (Cpd. No. 500)
Figure imgf000300_0001
Step 1: Synthesis of (2S)-tert-butyl 4-amino-2-methylpiperidine-1-carboxylate
Figure imgf000300_0002
[0325] Into a 10-L round-bottom flask was placed methanol (5 L), HCOONH4 (190 g, 3.01 mol, 37.80 equiv), acetic acid (5 g, 83.26 mmol, 1.04 equiv) and tert-butyl (2S)-2- methyl-4-oxopiperidine-1-carboxylate (17 g, 79.71 mmol, 1.00 equiv). Then NaBH3CN (10 g, 159.13 mmol, 2.00 equiv) was added into the mixture slowly. The resulting solution was stirred overnight at 25oC. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 500 mL of ethyl acetate. The resulting mixture was washed with 3x500 mL of brine (sat.). The resulting organic phase was concentrated under vacuum. This resulted in 15.5 g (91%) of tert-butyl (2S)-4-amino-2- methylpiperidine-1-carboxylate as off-white oil. LCMS (method A, ESI): RT=1.21min, m/z =215.1 [M+H]+. Step 2: Synthesis of (2S)-tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-2- methylpiperidine-1-carboxylate
Figure imgf000301_0001
[0326] Into a 1L round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed dichloromethane (500 mL), HOBT (15 g, 111.01 mmol, 1.53 equiv), EDCI (20 g, 104.33 mmol, 1.44 equiv), 5-cyclopropyl-1,2-oxazole-3-carboxylic acid (13.3 g, 86.85 mmol, 1.20 equiv) and tert-butyl (2S)-4-amino-2-methylpiperidine-1- carboxylate (15.5 g, 72.33 mmol, 1.00 equiv). Then triethylamine (36 g, 355.77 mmol, 4.92 equiv) was added dropwise. The resulting solution was stirred for 2 hours at 25oC. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 500 mL of ethyl acetate. The resulting mixture was washed with 3x500 mL of water. The resulting organic phase was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 14 g (55%) of tert-butyl (2S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1- carboxylate as light yellow oil. LCMS (method A, ESI): RT=2.05 min, m/z =350.2 [M+H]+.
Step 3: Synthesis of (2S,4S)-tert-butyl 4-(5-cyclopropylisoxazole-3- carboxamido)-2-methylpiperidine-1-carboxylate
Figure imgf000301_0002
[0327] The diastereomeric product was further purified by Chiral-HPLC with the following conditions: Column name: CHIRALPAK AD-H, 4.6*150mm,5um,Co-Solvent: EtOH(0.1%DEA), %Co-Solvent: Hexane,25.000, Detector: 220nm. The resulting solution was concentrated under vacuum. This resulted in 9.8 g (70%) of tert-butyl (2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate as colorless oil. 1H-NMR (400 MHz, DMSO): į 8.54-8.52 (m, 1H), 6.47 (s, 1H), 3.94- 3.87(m, 2H), 3.57-3.53(m, 1H), 3.32-3.26(m, 1H), 2.20-2.16(m, 1H), 1.80-1.63(m, 4H), 1.39(s, 9H), 1.16-1.15(m, 3H), 1.10-1.06(m, 2H), 0.93-0.89(m, 2H) ppm and 3.3 g (24%) of tert-butyl (2S,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1- carboxylate as a light yellow solid. 1H-NMR (400 MHz, DMSO): į 8.54-8.52 (m, 1H), 6.46 (s, 1H), 4.54-4.30(m, 1H), 4.28-4.04(m, 1H), 4.00-3.68(m, 1H), 3.10-2.70(m, 1H), 2.19-2.15(m, 1H), 1.76-1.73(m, 1H), 1.63-1.59(m, 2H), 1.39-1.35(m, 10H), 1.13-1.08(m, 5H), 1.00-0.82(m, 2H) ppm.
Step 4: Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole- 3-carboxamide hydrochloride
Figure imgf000302_0001
[0328] Into a 250-mL round-bottom flask was placed dichloromethane (100 mL) and tert-butyl (2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1- carboxylate (9.8 g, 28.05 mmol, 1.00 equiv). To the above hydrogen chloride (gas) was introduced into mixture. The resulting solution was stirred for 2 hours at 25oC. The resulting mixture was concentrated under vacuum. This resulted in 8.6 g of 5- cyclopropyl-N-[(2S,4S)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide
hydrochloride as a white solid. 1HNMR (400 MHz, MeOD): į 6.40(s, 1H), 4.24-4.10(m, 1H), 3.55-3.45(m, 1H), 3.40-3.35(m, 1H), 3.19-3.15(m, 1H), 2.24-2.15(m, 3H), 1.82- 1.77(m, 1H), 1.63-1.60(m, 1H),1.93-1.37(m, 3H), 1.21-1.13(m, 2H), 1.00-0.96(m, 2H) ppm. LCMS (method A, ESI): RT=1.13 min, m/z =250.1 [M-HCl+H]+.
Step 5: Synthesis of N-((2S,4S)-1-(3-chloropropylsulfonyl)-2-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000302_0002
[0329] Into a 25-mL round-bottom flask was placed dichloromethane (5 mL), triethylamine (121 mg, 1.20 mmol, 2.98 equiv) and 5-cyclopropyl-N-[(2S,4S)-2- methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide (100 mg, 0.40 mmol, 1.00 equiv). Then 3-chloropropane-1-sulfonyl chloride (106 mg, 0.60 mmol, 1.49 equiv) was added dropwise at 0oC. The resulting solution was stirred for 16 hours at 25oC. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/hexane (1:1). This resulted in 85 mg (54%) of N-[(2S,4S)-1-[(3- chloropropane)sulfonyl]-2-methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3- carboxamide as a white solid. 1H NMR (400 MHz, CD3OD): į 6.38(s, 1H), 4.13-4.01 (m, 1H), 3.80-3.72 (m, 3H) 3.66-3.65 (m, 1H) 3.26-3.19 (m, 3H), 2.19-2.00 (m, 3H) 2.04-1.98 (m, 2H) 1.77-1.70 (m, 2H), 1.43 (d, J=6.8Hz, 3H), 1.00-0.97 (m, 2H) , 1.16-1.12 (m, 2H)ppm. LCMS (method A, ESI): RT=1.37min, m/z =390.0 [M+H]+.
Step 6: Synthesis of N-((2S,4S)-1-(3-(benzylamino)propylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000303_0001
[0330] Into a 10mL round-bottom flask was placed 1,4-dioxane (3mL), N-[(2S,4S)-1-[(3- chloropropane)sulfonyl]-2-methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3- carboxamide (84 mg, 0.22 mmol, 1.00 equiv), and phenylmethanamine (274 mg, 2.56 mmol, 11.87 equiv). The resulting solution was stirred for 16 hours at 100oC. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/hexane (1:1). This resulted in 30.1 mg (30%) of N- [(2S,4S)-1-[[3-(benzylamino)propane]sulfonyl]-2-methylpiperidin-4-yl]-5-cyclopropyl- 1,2-oxazole-3-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD): į 7.37-7.29 (m, 5H), 6.38(s, 1H), 4.13-4.01 (m, 1H), 3.82(s, 2H), 3.80-3.78 (m, 1H), 3.62 (d, J=3.2Hz, 1H), 3.18-3.11(m, 3H), 2.78 (t, J=3.2Hz, 2H), 2.18-2.16 (m, 1H), 2.04-1.97 (m, 4H), 1.77-1.70 (m, 2H), 1.43 (d, J=6.8Hz, 3H), 1.00-0.97 (m, 2H), 1.16-1.12 (m, 2H) ppm. LCMS (method A, ESI): RT=1.48min, m/z =461.3 [M+H]+. EXAMPLE 16
Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(6-(2-morpholinoethylamino) pyridin- 3-ylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide dihydrochloride (Cpd. No. 458)
Figure imgf000303_0002
Step 1: Synthesis of N-((2S,4S)-1-(6-chloropyridin-3-ylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000304_0001
[0331] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide hydrochloride (200 mg, 0.69 mmol, 1.00 equiv). Then triethylamine (210 mg, 2.09mmol, 3.00 equiv) was added into dropwsie. The reaction mixture was cooled to 0 oC, then 6-chloropyridine-3-sulfonyl chloride (220 mg, 1.04 mmol, 1.50 equiv) was added dropwise. The resulting solution was stirred at room temperature for 15 h. The resulting mixture was washed by water (3[10ml), dried over Na2SO4 and concentrated under vacuum. This resulted in 296 mg (97%) of N-((2S,4S)-1-(6-chloropyridin-3- ylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide as light yellow solid. LCMS (method D, ESI): RT=1.47min, m/z =425 [M+H]+.
Step 2: Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(6-(2- morpholinoethylamino) pyridin-3-ylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide dihydrochloride
Figure imgf000304_0002
[0332] Into a 50-mL round-bottom flask was placed N-((2S,4S)-1-(6-chloropyridin-3- ylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide (296 mg, 0.69 mmol, 1.00 equiv), 2-morpholinoethanamine (226 mg, 1.74 mmol, 2.4 equiv) and 1,4-dioxane (5 mL). The resulting solution was stirred at 80oC for 15 h. The resulting mixture was purified by pre-HPLC. Column: X Select C18, 19x150 mm, 5 um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 5%B to 45%B in 11.5 min; 254nm. This resulting eluent was acidified by hydrochloric acid (6Nand concentrated resulting in 102.80 mg (28%) of 5-cyclopropyl-N-((2S,4S)-2- methyl-1-(6-(2-morpholinoethylamino)pyridin-3-ylsulfonyl)piperidin-4-yl)isoxazole-3- carboxamide dihydrochloride as light yellow solid. 1H-NMR (300 MHz, D2O): į 8.44 (s, 1H), 7.94 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 6.29(s, 1H), 4.14-3.08 (m, 16H), 2.12-2.08 (m, 1H), 1.97-1.86 (m, 2H), 1.64-1.79 (m, 2H), 1.26-1.24 (d, J = 6.0 Hz, 3H), 1.08-1.05(m, 2H), 0.99-0.74(m, 2H) ppm. LCMS (method D, ESI): RT=2.37 min, m/z =519.0 [M+H]+. EXAMPLE 17
Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-((piperidin-4- ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide (Cpd. No. 417)
and
5-cyclopropyl-N-((2R,4R)-2-methyl-1-((piperidin-4-ylmethyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide (Cpd. No. 418)
Figure imgf000305_0001
Step 1: Synthesis of tert-butyl 4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidine-1-carboxylate
Figure imgf000305_0002
[0333] To a solution of cis tert-butyl 4-amino-2-methylpiperidine-1-carboxylate (1 g, 4.67 mmol) and DIPEA (2.44 ml, 14 mmol) in DMF (25ml) was added 5-cyclopropyl- 1,2-oxazole-3-carboxylic acid (0.86 g, 5.6 mmol) followed by HATU (2.31 g, 6.07 mmol). The reaction was stirred at rt. LCMS analysis after ~1h showed a trace of SM and mainly product (72%, 1.33min, MNa+.=371.95). The reaction was poured into water (100ml) and the product was extracted with EtOAc (3x50ml). The combined organic layers were washed with water (2x50ml), brine (50ml), dried over Na2SO4, filtered and concentrated. The red oily residue was purified by Isolera over SiO2 (100g), eluting with a gradient of EtOAc in heptane from 5 to 50 % to yield 1.55 g (95%) of the amide as an amber viscous. TLC (25% EtOAc in Hept), rf:0.30.1H NMR (500 MHz, Chloroform-d) į 6.85 (d, J = 6.8 Hz, 1H), 6.31 (s, 1H), 4.21 (hept, J = 6.8, 6.1 Hz, 2H), 3.85 (ddd, J = 14.0, 5.5, 3.1 Hz, 1H), 3.13 (ddd, J = 14.3, 11.9, 3.9 Hz, 1H), 2.06 (ddd, J = 8.4, 4.9, 3.4 Hz, 1H), 2.02– 1.91 (m, 2H), 1.74– 1.66 (m, 2H), 1.45 (s, 9H), 1.25 (d, J = 7.2 Hz, 3H), 1.13– 1.08 (m, 2H), 1.00– 0.94 (m, 2H). LCMS analysis (METCR1673 Generic 2 minutes), 100%, 1.33min, [MNa]+.=372.00.
Step 2: Synthesis of 5-cyclopropyl-N-(2-methylpiperidin-4-yl)-1,2-oxazole-3- carboxamide hydrochloride
Figure imgf000306_0001
[0334] A solution of tert-butyl 4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidine-1-carboxylate (1.55 g, 4.44 mmol) in DCM (50ml) was treated with 4M HCl in dioxane (15 ml) at rt for ~4h. LCMS analysis showed complete reaction. The solvent was evaporated to dryness to yield 1.12 g (88%) of the amine as HCl salt as a white solid. 1H NMR (250 MHz, Methanol-d4) į 6.38 (s, 1H), 4.17 (tt, J = 11.9, 4.1 Hz, 1H), 3.53– 3.34 (m, 2H), 3.14 (td, J = 13.3, 3.1 Hz, 1H), 2.28– 2.08 (m, 3H), 1.94– 1.52 (m, 2H), 1.37 (d, J = 6.5 Hz, 3H), 1.20– 1.09 (m, 2H), 1.00– 0.91 (m, 2H). LCMS analysis (METCR1673 Generic 2 minutes), 100%, ~0.45 min, [MH-HCl]+.=250.00.
Step 3: Synthesis of benzyl 4-({[4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidin-1-yl]sulfonyl}methyl)piperidine-1-carboxylate
Figure imgf000306_0002
[0335] To a solution of 5-cyclopropyl-N-(2-methylpiperidin-4-yl)-1,2-oxazole-3- carboxamide hydrochloride (920 mg, 3.22 mmol) in DCM (40ml) was added DIPEA (3.37ml, 19.3 mmol) followed by benzyl 4-[(chlorosulfonyl)methyl]piperidine-1- carboxylate (1175 mg, 3.54 mmol) as a solution in DCM (10ml) and the reaction was left at rt overnight. The reaction was diluted with DCM (100ml) and washed with water (50ml) and brine (50ml). The combined aqueous layers were back-extracted with EtOAc (2x25ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by Isolera over SiO2 (100g), dry loaded and eluted with a gradient of EtOAc in heptane from 12 to 100% then with a gradient of MeOH in EtOAc from 0 to 20% to yield 0.92 g (47%) of sulfonamide as a white solid. TLC (2.5% MeOH in DCM), rf:0.30. 1H NMR (500 MHz, Chloroform-d) į 7.40– 7.28 (m, 5H), 6.77 (d, J = 7.4 Hz, 1H), 6.32 (s, 1H), 5.12 (s, 2H), 4.20 (ddt, J = 16.0, 7.7, 4.5 Hz, 3H), 3.76– 3.63 (m, 2H), 3.21 (ddd, J = 13.5, 7.4, 3.8 Hz, 1H), 2.83 (hept, J = 6.4 Hz, 4H), 2.24– 1.90 (m, 6H), 1.79– 1.69 (m, 2H), 1.44 (d, J = 6.9 Hz, 3H), 1.33– 1.22 (m, 2H), 1.16– 1.09 (m, 2H), 1.01 – 0.96 (m, 2H). LCMS analysis (METCR1673 Generic 2 minutes), 100%, 1.38 min, [MH]+.=545.00.
Step 4: Synthesis of 5-cyclopropyl-N-[2-methyl-1-(piperidin-4- ylmethanesulfonyl) piperidin-4-yl]-1,2-oxazole-3-carboxamide
Figure imgf000307_0001
[0336] To a solution of benzyl 4-({[4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidin-1-yl]sulfonyl}methyl)piperidine-1-carboxylate (90%, 917 mg, 1.52 mmol) in MeCN (50ml) and DCM (5ml) was added TMS-I (647 μl, 4.55 mmol) at rt for 1h. The solution was then added onto 50ml of 0.5M HCl in MeOH and the mixture was stirred at rt for an additional ~2h. The solvent was evaporated and the residue was purified by Isolute SCX-2 (10g cartridge) eluted with MeOH (15x10ml) then with 7N NH3 in MeOH to yield 636 mg (96%) of 5-cyclopropyl-N-(2-methyl-1-((piperidin-4- ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide as a white solid. 1H NMR (500 MHz, Chloroform-d) į 6.79 (d, J = 7.2 Hz, 1H), 6.32 (s, 1H), 4.20 (ddq, J = 12.0, 7.7, 4.6 Hz, 1H), 3.74– 3.64 (m, 2H), 3.21 (ddd, J = 13.4, 7.4, 3.8 Hz, 1H), 3.09 (d, J = 12.3 Hz, 2H), 2.83 (h, J = 6.9, 6.3 Hz, 2H), 2.70– 2.63 (m, 2H), 2.06 (dddt, J = 17.4, 13.0, 8.2, 5.1 Hz, 4H), 1.94 (d, J = 12.5 Hz, 2H), 1.73 (dt, J = 13.7, 6.3 Hz, 5H), 1.45 (d, J = 6.9 Hz, 3H), 1.37– 1.26 (m, 2H), 1.14– 1.09 (m, 2H), 1.00– 0.96 (m, 2H). LCMS analysis (METCR1673 Generic 2 minutes), 94%, 0.90 min, [MH]+.=411.00.
Step 5: Chiral separation of 5-cyclopropyl-N-[2-methyl-1-(piperidin-4- ylmethanesulfon l i eridin-4- l -1,2-oxazole-3-carboxamide
Figure imgf000307_0002
[0337] The racemic mixture of 5-cyclopropyl-N-(2-methyl-1-((piperidin-4- ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide (94%, 636 mg, 1.46 mmol) of the cis isomers were purified by chiral separation using the following conditions: 25% Methanol + 0.1% DEA: 80% CO2 with Chiralpak AD-H 25cm column at 15ml/min. 254 mg (43%) of racemic mixture was recovered. 118 mg (20%) of 5-cyclopropyl-N- ((2S,4S)-2-methyl-1-((piperidin-4-ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide (arbitrarily assigned as (S,S)-isomer) was isolated at 100% ee, having a retention time on chiral column of 3.21 min.1H NMR (500 MHz, Methanol-d4) į 6.36 (s, 1H), 4.10 (tt, J = 9.1, 4.6 Hz, 1 H), 3.77 (ddd, J = 13.4, 6.7, 4.0 Hz, 1H), 3.63– 3.55 (m, 1H), 3.15 (ddd, J = 13.2, 8.5, 3.7 Hz, 1H), 3.07– 3.02 (m, 2H), 3.01– 2.93 (m, 2H), 2.63 (td, J = 12.5, 2.7 Hz, 2H), 2.15 (tt, J = 8.5, 5.0 Hz, 1H), 2.12– 1.90 (m, 5H), 1.77– 1.67 (m, 2H), 1.41 (d, J = 6.7 Hz, 3H), 1.33 (qd, J = 12.0, 3.6 Hz, 2H), 1.16– 1.10 (m, 2H), 0.98– 0.94 (m, 2H). LCMS analysis (METCR1416 Hi res 7 min), 100%, 2.74 min, [MH]+.=411.00. 119 mg (19%) of 5-cyclopropyl-N-((2R,4R)-2-methyl-1-((piperidin-4- ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide (arbitrarily assigned as (R,R) isomer) was isolated at 96% ee, having a retention time on chiral column of 4.77 min. 1H NMR (500 MHz, Methanol-d4) į 6.36 (s, 1H), 4.10 (tt, J = 9.1, 4.6 Hz, 1H), 3.77 (ddd, J = 13.4, 6.7, 4.0 Hz, 1H), 3.63– 3.55 (m, 1H), 3.15 (ddd, J = 13.0, 8.5, 3.7 Hz, 1H), 3.04 (d, J = 12.7 Hz, 2H), 3.02– 2.93 (m, 2H), 2.64 (td, J = 12.5, 2.6 Hz, 2H), 2.15 (tt, J = 8.4, 5.0 Hz, 1H), 2.12– 1.91 (m, 5H), 1.77– 1.67 (m, 2H), 1.41 (d, J = 6.7 Hz, 3H), 1.33 (qd, J = 12.0, 3.1 Hz, 2H), 1.15– 1.11 (m, 2H), 0.98– 0.94 (m, 2H). LCMS analysis (METCR1416 Hi res 7 min), 100%, 2.74 min, [MH]+.=410.95. EXAMPLE 18
Synthesis of 5-cyclopropyl-N-((1R, 3r, 5S)-8-(piperidin-4-ylmethylsulfonyl)-8-aza- bicyclo [3.2.1] octan-3-yl) isoxazole-3-carboxamide (Cpd. No. 543)
Figure imgf000308_0001
Step 1: Synthesis of benzyl 4-(((1S,3r,5R)-3-(5-cyclopropylisoxazole-3- carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate
Figure imgf000309_0001
[0338] Into a 25-mL round-bottom flask was placed N-((1S,3R,5R)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (80 mg, 0.27 mmol, 1.00 equiv), dichloromethane (5 mL), TEA (81 mg, 0.80 mmol, 3.00 equiv), and 4-dimethylaminopyridine (33 mg, 0.27 mmol, 1.00 equiv). This was followed by the addition of benzyl 4-[(chlorosulfonyl)methyl]piperidine-1-carboxylate (140 mg, 0.42 mmol, 1.50 equiv) dropwise at 0oC. The resulting solution was stirred for 4 h at 25oC. The reaction was quenched with water/ice (20 mL) and extracted with EA (20mL, three times). The organic extracts were combined and washed with brine (20mL), then dried over with Na2SO4. After evaporation, the residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2:3). This resulted in 70 mg (47%) of benzyl 4-(((1S, 3R, 5R)-3-(5-cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo [3.2.1] octan- 8-ylsulfonyl) methyl) piperidine-1-carboxylate as a yellow solid. LCMS (method A, ESI): RT = 1.09 min, m/z = 557.0 [M+H]+.
Step 2: Synthesis of 5-cyclopropyl-N-((1R, 3rR, 5S)-8-(piperidin-4- ylmethylsulfonyl)-8-aza-bicyclo [3.2.1] octan-3-yl) isoxazole-3-carboxamide
Figure imgf000309_0002
[0339] Into a 25-mL round-bottom flask was placed benzyl 4-(((1S, R, 5R)-3-(5- cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo [3.2.1] octan-8-ylsulfonyl) methyl) piperidine-1-carboxylate (70 mg, 0.13 mmol, 1.00 equiv) and hydrochloric acid (12N, 3mL). The resulting solution was stirred for 2 h at 25oC. The residue was concentrated under vacuum. The crude product (32.9 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase: (phase A: 0.5% NH4HCO3 in H2O, phase B: CH3CN) B/A=5% increasing to B/A=80% within 15 min; Detector, UV 254 nm. This resulted in 14.4 mg (27%) of 5-cyclopropyl-N-((1S, 3R, 5R)- 8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo [3.2.1] octan-3-yl) isoxazole-3- carboxamide as a white solid. 1H-NMR (400 MHz, CD3OD): į6.48(s, 1H), 4.56(s, 2H), 4.20-4.16(m, 1H), 3.34-3.02(m, 4H), 2.66-2.59(m, 2H), 2.31-1.92(m, 12H), 1.34-1.30(m, 2H), 1.18-1.13(m, 2H), 1.01-0.97(m, 2H) ppm. LCMS (method A, ESI): RT = 1.36 min, m/z = 423.3 [M+H]+. EXAMPLE 19
Synthesis of N-((2S,4S)-1-(4-aminopiperidin-1-ylsulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide trifluoroacetic acid (Cpd. No. 529)
Figure imgf000310_0001
Step 1: Synthesis of 1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonyl chloride
Figure imgf000310_0002
[0340] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed dichloromethane (30 mL) and sulfuryl chloride (5.1 g, 37.79 mmol, 1.08 equiv). This was followed by the addition of a solution of 1,4-dioxa-8- azaspiro[4.5]decane (5 g, 34.92 mmol, 1.00 equiv) and 4-dimethylaminopyridine (4.27 g, 34.95 mmol, 1.00 equiv) in dichloromethane (10 mL) dropwise with stirring at -78oC. The resulting solution was stirred for 4 hours at 25oC. The resulting mixture was concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/ petroleum ether (1:10). This resulted in 4.2 g (50%) of 1,4-dioxa-8- azaspiro[4.5]decane-8-sulfonyl chloride as a white solid. 1H NMR (400 MHz, CDCl3) G: 4.02(s, 4H), 3.51(s, 4H), 1.94-1.91(m, 4H) ppm.
Step 2: Synthesis of 5-cyclopropyl-N-[(2S,4S)-1-[1,4-dioxa-8- azaspiro[4.5]decane-8-sulfon l -2-meth l i eridin-4- l -1,2-oxazole-3-carboxamide O N O
Figure imgf000310_0003
[0341] Into a 50-mL round-bottom flask was placed dichloromethane (15 mL), triethylamine (500 mg, 4.94 mmol, 4.71 equiv), and 5-cyclopropyl-N-[(2S,4S)-2- methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide hydrochloride (300 mg, 1.05 mmol, 1.00 equiv). This was followed by the addition of a solution of 1,4-dioxa-8- azaspiro[4.5]decane-8-sulfonyl chloride (700 mg, 2.90 mmol, 2.76 equiv) in dichloromethane (5 mL) dropwise with stirring at -78oC. The resulting solution was stirred for 16 hours at 25oC. The reaction mixture was washed with brine (sat. aq., 3 x 10 mL) and the organic layerconcentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (3:7). This resulted in 300 mg (63%) of 5-cyclopropyl-N-[(2S,4S)-1-[1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonyl]-2- methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide as a white solid. 1H NMR (400 MHz, CDCl3) G : 6.82(d, J=7.2 Hz, 1H), 6.34(s, 1H), 4.24-4.22(m, 1H), 3.98(s, 4H), 3.73- 3.70(m, 1H), 3.63-3.60(m, 1H), 3.35-3.27(m, 5H), 2.11-2.00(m, 3H), 1.80-1.73(m, 6H), 1.45(d, J=6.8Hz, 3H), 1.16-1.12(m, 2H), 1.02-0.98(m, 2H) ppm. LCMS (method D, ESI): RT =1.91 min, m/z = 455.5 [M+H]+.
Step 3: Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-oxopiperidin-1- ylsulfonyl)piperidin-4-yl isoxazole-3-carboxamide
Figure imgf000311_0001
[0342] Into a 25-mL round-bottom flask was placed THF (10 mL), 5-cyclopropyl-N- [(2S,4S)-1-[1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonyl]-2-methylpiperidin-4-yl]-1,2- oxazole-3-carboxamide (300 mg, 0.66 mmol, 1.00 equiv) and hydrochloric acid (2N, 5 mL). The resulting solution was stirred for 16 hour at 25oC. The pH value of the solution was adjusted to 8 with Na2CO3 (sat. aq.). The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with 10 mL of DCM. The solids were filtered off yielding250 mg (92%) of 5-cyclopropyl-N-[(2S,4S)-2-methyl-1-(4-oxopiperidine-1- sulfonyl)piperidin-4-yl]-1,2-oxazole-3-carboxamide as a white solid. 1H NMR (400 MHz, CDCl3) G : 6.83 (d, J=6.38Hz, 1H), 6.34(s, 1H), 4.26-4.24(m, 1H), 3.72-3.66(m, 2H), 3.59-3.56(m, 4H), 3.34-3.32(m, 1H), 2.60-2.56(m, 4H), 2.11-2.04(m, 3H), 1.82- 1.76(m, 2H), 1.48 (d, J=6.8Hz, 3H), 1.15-1.12(m, 2H), 1.02-1.00(m, 2H) ppm. LCMS (method D, ESI): RT =1.32 min, m/z = 411.2 [M+H]+.
Step 4: Synthesis of N-((2S,4S)-1-(4-aminopiperidin-1-ylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide trifluoroacetic acid
Figure imgf000312_0001
[0343] Into a 250-mL round-bottom flask was placed methanol (100 mL), 5-cyclopropyl- N-[(2S,4S)-2-methyl-1-(4-oxopiperidine-1-sulfonyl)piperidin-4-yl]-1,2-oxazole-3- carboxamide (60 mg, 0.15 mmol, 1.00 equiv), and ammonium formate (500 mg, 7.93 mmol, 54.25 equiv). Then NaBH3CN (30 mg, 0.48 mmol, 3.27 equiv) was added at 0oC. The resulting solution was stirred for 16 hours at 25oC. The reaction mixture was concentrated under vacuum and the residuediluted with 20 mL of dichloromethane. The resulting mixture was washed with brine (sat. aq., 2 x 10 mL). The organic layer was concentrated under vacuum and the crude product purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)): Column, Atlantis Prep OBD T3 Column,19*150mm,5um,; mobile phase, water with 0.05% TFA and CH3CN ( up to 3.0% in 10 min, up to 100.0% in 1 min, hold 100.0% in 1 min); Detector, UV 254 nm. This resulted in 26.4 mg (34%) of N-[(2S,4S)-1-(4-aminopiperidine-1-sulfonyl)-2- methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide trifluoroacetate as a white solid. 1H NMR (400 MHz, CD3OD) G : 6.38(s, 1H), 4.13-4.05(m, 1H), 3.80- 3.77(m, 3H), 3.76-3.74(m, 1H), 3.33-3.23(m, 2H), 2.93(t, J=12.4Hz, 2H), 2.19-2.15(m, 1H), 2.07-1.95(m, 4H), 1.82-1.67(m, 4H), 1.42 (d, J=6.8Hz, 3H), 1.18-1.13(m, 2H), 1.00- 0.97(m, 2H) ppm. LCMS (method A, ESI): RT =1.71 min, m/z = 412.5 [M-TFA+H]+. EXAMPLE 20
Synthesis of N-((2S,4S)-1-(4-(2-aminopropan-2-yl)phenylsulfonyl)-2-methylpiperidin-4- yl)-5-c clo ro lisoxazole-3-carboxamide C d. No. 541)
Figure imgf000312_0002
Step 1: Synthesis of N-((2S,4S)-1-(4-bromophenylsulfonyl)-2-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000312_0003
[0344] Into a 100-mL round-bottom flask was placed 5-cyclopropyl-N-[(2S,4S)-2- methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide hydrochloride (1 g, 3.50 mmol, 1.00 equiv) and dichloromethane (10 mL). This was followed by the dropwise addition of TEA (1.1 g, 10.87 mmol, 3.11 equiv) with stirring at 0oC. To this was added 4- bromobenzene-1-sulfonyl chloride (900 mg, 3.52 mmol, 1.01 equiv) in several batches at 0oC. The resulting solution was stirred at room temperature for overnight. The reaction mixture was diluted with 10 mL of H2O andextracted with 3x20 mL of dichloromethane. Theorganic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:10-1:2). This resulted in 1.6 g (98%) of N-((2S,4S)- 1-(4-bromophenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide as a white solid. 1H-NMR (400 MHz, CDCl3): į 7.75-7.64 (m, 4H), 6.75 (d, J =6.4 Hz, 1H), 6.32 (s, 1H), 4.17-4.03 (m, 1H), 3.80-3.69 (m, 1H), 3.67-3.53 (m, 1H), 3.30-3.18 (m, 1H), 2.12-2.03 (m, 1H), 2.03-1.92 (m, 2H), 1.82-1.66 (m, 2H), 1.33 (d, J =6.8 Hz, 3H), 1.19-1.09 (m, 2H), 1.03-0.95 (m, 2H) ppm. LCMS (Method A, ESI): RT=1.54 min, m/z =468.0 [M+H]+.
Step 2: Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-(prop-1-en-2- yl)phenylsulfonyl)piperidin-4- l isoxazole-3-carboxamide
Figure imgf000313_0001
[0345] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed N-((2S,4S)-1-(4-bromophenylsulfonyl)-2-methylpiperidin-4-yl)- 5-cyclopropylisoxazole-3-carboxamide (1 g, 2.14 mmol, 1.00 equiv), Pd(dppf)Cl2 (160 mg, 0.22 mmol, 0.10 equiv), K2CO3 (880 mg, 6.32 mmol, 2.96 equiv), 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (540 mg, 3.21 mmol, 1.51 equiv), 1,4-dioxane (10 mL) and water(1 mL). The resulting solution was stirred at 90oC overnight. The reaction mixture was diluted with 10 mL of H2O andextracted with 3x50 mL of ethyl acetate. Theorganic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:10-1:2). This resulted in 480 mg (52%) of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-(prop-1-en-2-yl)phenylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide as a light yellow solid. 1H-NMR (300 MHz, CDCl3): į 7.76 (d, J =8.7 Hz, 2H), 7.58 (d, J =8.7 Hz, 2H), 6.73 (d, J =6.6 Hz, 1H), 6.30 (s, 1H), 5.48 (s, 1H), 5.24 (s, 1H), 4.17-3.98 (m, 1H), 3.81-3.68 (m, 1H), 3.61-3.47 (m, 1H), 3.28-3.12 (m, 1H), 2.18 (s, 3H), 2.11-1.92 (m, 3H), 1.79-1.60 (m, 2H), 1.33 (d, J =6.6 Hz, 3H), 1.16-1.05 (m, 2H), 1.02-0.91 (m, 2H) ppm. LCMS (Method D, ESI): RT=1.61 min, m/z =430.0 [M+H]+.
Step 3: Synthesis of N-((2S,4S)-1-(4-(2-(2-chloroacetamido)propan-2- yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000314_0001
[0346] Into a 100-mL round-bottom flask was placed 5-cyclopropyl-N-((2S,4S)-2- methyl-1-(4-(prop-1-en-2-yl)phenylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide (480 mg, 1.12 mmol, 1.00 equiv), 2-chloroacetonitrile (1.67 g, 22.12 mmol, 19.79 equiv), and acetic acid (28 mL). After cooling to 0oC sulfuric acid (98%, 7 mL) was added dropwise. The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with of ice-water and the pH of the solution was adjusted to 7 with sodium carbonate (sat. aq.). The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The residue was chromatographed on a silica gel column with dichloromethane/methanol (20:1). This resulted in 580 mg (99%) of N-((2S,4S)-1-(4-(2- (2-chloroacetamido)propan-2-yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide as a white solid. 1H-NMR (300 MHz, CD3OD): į 7.78 (d, J =8.7 Hz, 2H), 7.62 (d, J =8.7 Hz, 2H), 6.34 (s, 1H), 4.09-3.99 (m, 3H), 3.95- 3.80 (m, 2H), 3.17-3.00 (m, 1H), 2.20-2.08 (m, 1H), 2.03-1.79 (m, 2H), 1.77-1.56 (m, 8H), 1.33 (d, J =6.6 Hz, 3H), 1.19-1.09 (m, 2H), 1.00-0.91 (m, 2H) ppm. LCMS (Method D, ESI): RT=0.97 min, m/z =523.0 [M+H]+.
Step 4: Synthesis of N-((2S,4S)-1-(4-(2-aminopropan-2-yl)phenylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000315_0001
[0347] Into a 25-mL round-bottom flask was placed N-((2S,4S)-1-(4-(2-(2- chloroacetamido)propan-2-yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide (150 mg, 0.29 mmol, 1.00 equiv), acetic acid (0.3 mL), ethanol (1.5 mL) and thiourea (26 mg, 0.34 mmol, 1.19 equiv). The resulting solution was stirred at 85oC overnight. The reaction mixture was concentrated under vacuum and the residue diluted with 10 mL of H2O. The resulting solution was extracted with 3x5 mL of ethyl acetate and the organic layers combined. The combined extracts were concentrated under vacuum and the crude product (98 mg) was purified by Prep- HPLC with the following conditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/10mmol/L NH4HCO3, Mobile Phase B: MeOH; Flow rate: 30 mL/min; Gradient: 45%B to 75%B in 06 min; 254nm. 100 mL product was obtained. This resulted in 24 mg (19%) of N-((2S,4S)-1-(4-(2-aminopropan-2-yl)phenylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide as a white solid. 1H-NMR (400 MHz, CD3OD): į 7.85-7.71 (m, 4H), 6.35 (s, 1H), 3.92-3.80 (m, 2H), 3.41-3.33 (m, 1H), 3.16-3.07 (m, 1H), 2.21-2.10 (m, 1H), 2.00-1.91 (m, 1H), 1.91-1.82 (m, 1H), 1.76- 1.62 (m, 2H), 1.54 (s, 6H), 1.34 (d, J =6.4 Hz, 3H), 1.19-1.09 (m, 2H), 1.00-0.91 (m, 2H) ppm. LCMS (Method B, ESI): RT=1.71 min, m/z =447.0 [M+H]+. EXAMPLE 21
Synthesis of 5-cyclopropyl-N-[(1R,3r,5S)-8-([[1-(4,4,4-trifluorobutyl)piperidin-4- yl]methane]sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide (Cpd.
No. 528)
Figure imgf000315_0002
[0348] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 5-cyclopropyl-N-[(1R,3R,5S)-8-[(piperidin-4- ylmethane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide (68 mg, 0.16 mmol, 1.00 equiv), methanol (2 mL), and 4,4,4-trifluorobutanal (41 mg, 0.33 mmol, 2.00 equiv). Then NaBH3CN (51 mg, 5.00 equiv) was added at 0oC. The resulting solution was stirred for 6 h at room temperature. The reacton mixture was concentrated under vacuum. The residue was dissolved in DCM (10 mL) and washed with saturated brine (10 mL). The organic phase was collected and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC- 019): Column, XBridge Prep C18 OBD Column, 19*100mm 5um 13nm; mobile phase, Water with 10mmolNH4HCO3 and MeCN (30.0% MeCN up to 60.0% in 6 min); Detector, UV 254/220nm. This resulted in 23.6 mg (28%) of 5-cyclopropyl-N- [(1R,3R,5S)-8-([[1-(4,4,4-trifluorobutyl)piperidin-4-yl]methane]sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide as a white solid. 1H-NMR (400 MHz, CD3OD): 6.39(s, 1H), 4.25(s, 2H), 4.17(t, J = 6.8 Hz, 1H), 3.07(d, J = 5.6 Hz, 2H), 2.96(d, J = 11.6 Hz, 2H), 2.43(t, J = 7.6 Hz, 2H), 2.31-1.97(m, 16H), 1.81-1.74(m, 2H), 1.46(q, J = 12.4 Hz, 2H), 1.18-1.13(m, 2H), 1.00-0.95(m, 2H) ppm. LCMS (method A, ESI): RT = 1.52 min, m/z = 533.4 [M+H]+. EXAMPLE 22
Synthesis of N-((2S,4S)-1-(3,8-diaza-bicyclo[3.2.1]octan-8-ylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide (Cpd. No. 555)
Figure imgf000316_0001
Step 1: Synthesis of (2S,4S)-4-(5-cyclopropylisoxazole-3-carboxamido)-2- methylpiperidine-1-sulfonyl chloride
Figure imgf000316_0002
[0349] Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed solution of sulfuryl chloride (242 mg, 1.79 mmol, 1.50 equiv) in dichloromethane (10 mL) at -70oC. To this was added a solution of DIEA (621 mg, 4.81 mmol, 4.00 equiv) and 5-cyclopropyl-N-(3-methylpiperazin-1-yl)-1,2- oxazole-3-carboxamide (300 mg, 1.20 mmol, 1.00 equiv) in dichloromethane (5 mL) dropwise with stirring at -70oC. The resulting solution was stirred for 30 min at -70oC in a dry ice bath. The reaction mixture was concentrated under vacuum and theresidue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:4). The fractions containing product were combined and concentrated under vacuum. This resulted in 350 mg (84%) of 4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperazine- 1-sulfonyl chloride as a white solid. LCMS (method D, ESI): RT = 0.98 min, m/z = 348 [M+H]+.
Step 2: Synthesis of tert-butyl 8-((2S,4S)-4-(5-cyclopropylisoxazole-3- carboxamido)-2-methylpiperidin-1-ylsulfonyl)-3,8-diaza-bicyclo[3.2.1]octane-3- carboxylate
Figure imgf000317_0001
[0350] Into a 50-mL round-bottom flask was placed tert-butyl 3,8- diazabicyclo[3.2.1]octane-3-carboxylate (366.6 mg, 1.73 mmol, 1.50 equiv), dichloromethane (20 mL), DIEA (298 mg, 2.31 mmol, 2.00 equiv), and 4- dimethylaminopyridine (14 mg, 0.11 mmol, 0.10 equiv). To this was added a solution of (2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-sulfonyl chloride (400 mg, 1.15 mmol, 1.00 equiv) in dichloromethane (2mL) dropwise with stirring at 0oC under nitrogen. The resulting solution was stirred overnight at room temperature. After concentration, the residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/10-1/5). This resulted in 550 mg (91%) of tert-butyl 8- [(2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-sulfonyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate as colorless oil. LCMS (method D, ESI): RT = 1.26 min, m/z = 524.3 [M+H]+.
Step 3: Synthesis of 5-cyclopropyl-N-[(2S,4S)-1-[3,8-diazabicyclo[3.2.1]octane- 8-sulfonyl]-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide
Figure imgf000318_0001
[0351] Into a 50-mL round-bottom flask was placed tert-butyl 8-[(2S,4S)-4-(5- cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-sulfonyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (550 mg, 1.05 mmol, 1.00 equiv), dichloromethane (20 mL) and trifluoroacetic acid (4 mL). The resulting solution was stirred for 2.5 h at room temperature. The reaction mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, Sunfire C18 19*150, mobile phase, CH3CN:NH4CO3/H2O (10mmol/L) = 20%- 55%, 20min, Detector UV 254nm. This resulted in 355.4 mg (80%) of 5-cyclopropyl-N- [(2S,4S)-1-[3,8-diazabicyclo[3.2.1]octane-8-sulfonyl]-2-methylpiperidin-4-yl]-1,2- oxazole-3-carboxamide as a white solid. 1H-NMR (300 MHz, CDCl3): į 6.90-6.71 (m, 1H), 6.32 (s, 1H), 4.28-4.15(m, 1H), 3.78-3.68(m, 1H), 3.67-3.50(m, 3H), 3.4 -3.28(m, 2H), 3.27-3.15 (m, 1H), 3.10-3.00(m, 2H), 2.20-2.00(m, 4H), 1.89-1.69(m, 6H), 1.50- 1.39(m, 3H), 1.20-1.06(m, 2H) , 1.05-0.90(m, 2H) ppm. LCMS (method A, ESI): RT = 1.73 min, m/z = 424.0 [M+H]+. EXAMPLE 23
Synthesis of N-((1R,3R,5S)-8-((1r,4R)-4-aminocyclohexylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride
(Cpd. No. 539)
Figure imgf000318_0002
Step 1: Synthesis of 5-cyclopropyl-N-((1R,3r,5S)-8-(4-oxocyclohexylsulfonyl)- 8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide
Figure imgf000318_0003
[0352] Into a 2-L 3-necked round-bottom flask was placed a solution of N-((1R,3r,5S)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (20 g, 67.16 mmol, 1.00 equiv) in dichloromethane (800 mL). Then DIEA (43 g, 332.71 mmol, 5.00 equiv) was added, followed by the addition of 4-oxocyclohexane-1-sulfonyl chloride (14.45 g, 73.48 mmol, 1.10 equiv) in portions over 5.5 hr (0.1 equiv for each portion ). The resulting solution was stirred overnight at 20oC. The reaction mixture was washed with dilute hydrochloric acid (1N, 200 mL). Then the organic phase was washed with NaHCO3 (sat. 200 mL) and brine (sat. 200 mL) respectively. The organic phase was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 19 g (64%) of 5-cyclopropyl-N-((1R,3r,5S)-8-(4-oxocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide as a yellow solid. 1H-NMR (300 MHz, CDCl3): į 7.14(d, J = 9 Hz, 1H), 6.34(s, 1H), 4.37-4.25(m, 3H), 3.36-3.27(m, 1H), 2.65-2.15(m, 10H), 2.13- 1.9(m, 7H), 1.20-1.10(m, 2H), 1.05-0.95(m, 2H) ppm. LCMS (method C, ESI): RT = 0.88 min, m/z = 422.2 [M+H]+.
Step 2: Synthesis of N-((1R,3R,5S)-8-(((1r,4R)-4-aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride
Figure imgf000319_0001
[0353] Into a 5-L round-bottom flask was placed a solution of 5-cyclopropyl-N- ((1R,3r,5S)-8-(4-oxocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide (3 g, 7.12 mmol, 1.00 equiv) in methanol (3 L), then HCOONH4 (17.6 g, 279.12 mmol, 40.00 equiv) and acetic acid (852 mg, 14.19 mmol, 2.00 equiv) were added. After stirred for 30 min at 25oC, NaBH3CN (895 mg, 14.24 mmol, 2.00 equiv) was added portion-wise. The resulting solution was stirred for 30 min at 25oC. The reaction mixture was concentrated under vacuum. The resulting solid was extracted with ethyl acetate (100 mLx5). The combined organic extracts were concentrated and the residue purified by flash chromatography (DCE: MeOH = 10:1). The crude product was further purified by Prep-HPLC with the following conditions: Column, X Bridge C18, 19*150 mm, 5 um; mobile phase, Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 20 mL/min; Detector, 254 nm. The fractions containing product were combined and concentrated. They were then treated with hydrochloric acid (12N, 1 mL) and concentrated again under vacuum. This resulted in 1.0 g (31%) of N-((1R,3R,5S)-8- ((1r,4R)-4-aminocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide hydrochloride as a light yellow solid. 1H-NMR (300 MHz, D2O): į 6.29(s, 1H), 4.21-4.00(m, 3H), 3.28-3.10(m, 2H), 2.30-2.05(m, 7H), 2.05-1.87(m, 6H), 1.65-1.35(m, 4H), 1.12-1.00(m, 2H), 0.95-0.84(m, 2H) ppm. LCMS (method D, ESI): RT = 0.89 min, m/z =423.1 [M+H]+. EXAMPLE 24
Synthesis of N-((1R,3r,5S)-8-(4-aminopiperidin-1-ylsulfonyl)-8-aza-bicyclo[3.2.1]octan- 3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (Cpd. No. 532)
Figure imgf000320_0001
Step 1: Synthesis of tert-butyl 1-((1R,3r,5S)-3-(5-cyclopropylisoxazole-3- carboxamido)-8-aza-bic clo 3.2.1 octan-8- lsulfon l i eridin-4-ylcarbamate
Figure imgf000320_0002
[0354] Into a 250-mL round-bottom flask was placed tert-butyl N-(piperidin-4- yl)carbamate (1.2 g, 5.99 mmol, 4.00 equiv), dichloromethane (20 mL), and DIEA (2.2 g, 17.02 mmol, 10.00 equiv). After stirring for 30 min, (1R,3r,5S)-3-(5-cyclopropyl-1,2- oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl chloride (600 mg, 1.67 mmol, 1.00 equiv) was added at 0oC. The resulting solution was stirred for 12 h at 20oC. The reaction mixture was diluted by DCM (30 mL), and washed by water (10 mLx3). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/hexane (2:1 ). This resulted in 620 mg (71%) of tert-butyl 1-((1 R,3r,5S)-3-(5- cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)piperidin- 4-ylcarbamate. 1H-NMR (400 MHz,CDCl3): į 7.15(d, J = 7.2 Hz, 1H), 6.35(s, 1H), 4.50- 4.45(m, 1H), 4.36-4.28(m, 1H), 4.20-4.10(m, 2H), 3.75-3.50(m, 3H), 2.90-2.80(m, 2H), 2.35-2.22(m, 4H), 2.15-1.89(m, 7H), 1.55-1.43(m, 11H), 1.18-1.12(m, 2H), 1.04-0.96(m, 2H) ppm. LCMS (method A, ESI): RT = 1.45 min, m/z = 546.0 [M+23]+.
Step 2: Synthesis of N-((1R,3r,5S)-8-(4-aminopiperidin-1-ylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride
Figure imgf000321_0001
[0355] Into a 250-mL round-bottom flask was placed tert-butyl N-[1-[(1R,3r,5S)-3-(5- cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4- yl]carbamate (600 mg, 1.15 mmol, 1.00 equiv) and dichloromethane (20 mL). Then hydrogen chloride (gas) was introduced into mixture. The resulting solution was stirred for 5 h at 20oC. The resulting mixture was concentrated under vacuum. The solids were collected by filtration. This resulted in 420 mg (87%) of N-((1R,3r,5S)-8-(4- aminopiperidin-1-ylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3- carboxamide hydrochloride as a white solid. 1H-NMR (300 MHz,D2O): į 6.31(s, 1H), 4.09(s, 3H), 3.76(d, J = 9 Hz, 2H), 3.39-3.26(m, 1H), 2.97-2.84(m, 2H), 2.30-1.90(m, 11H), 1.74-1.56(m, 2H), 1.15-1.02(m, 2H), 0.96-0.86(m, 2H) ppm. LCMS (method B, ESI): RT=1.50 min, m/z =423.9 [M+H]+. EXAMPLE 25
Synthesis of N-((1R,3r,5S)-8-(2,7-diazaspiro[3.5]nonan-2-ylsulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 2,2,2- trifluoroacetate (Cpd. No. 559)
Figure imgf000321_0002
Step 1: Synthesis of (1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8- azabicyclo[3.2.1]octane-8-sulfonyl chloride
Figure imgf000322_0001
[0356] Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed sulfuryl chloride (451 mg, 3.34 mmol, 1.00 equiv). At -78oC, DIEA (870 mg, 6.73 mmol, 2.00 equiv) with N-[(1R,3r,5S)-8- azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride (1 g, 3.36 mmol, 1.00 equiv) in dichloromethane (50 mL) was added dropwise into the above solution at -78oC (in a liquid nitrogen bath) in 5 min. The resulting solution was allowed to warm to room temperature and stir overnight. The reaction mixture was concentrated under vacuum. The residue was dissolved in 40 ml of ethyl acetate. The resulting mixture was washed with 50 mL of diluted hydrochloric acid (1N). Then the mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1 g (83%) of (1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8- azabicyclo[3.2.1]octane-8-sulfonyl chloride as a white solid. 1H-NMR (300 MHz, CD3OD): į 6.36(s, 1H), 4.45(s, 2H), 4.17(t, J = 12 Hz, 1H), 2.50-2.02(m, 9H), 1.17- 1.09(m, 2H), 1.00-0.91(m, 2H) ppm. LCMS (method A, ESI): RT=1.45 min, m/z =360.0 [M+H]+.
Step 2: Synthesis of tert-butyl 2-[(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3- amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate
Figure imgf000322_0002
[0357] Into a 50-mL round-bottom flask was placed tert-butyl 2,7-diazaspiro[3.5]nonane- 7-carboxylate hydrochloride (876 mg, 3.33 mmol, 4.14 equiv), DIEA (1.07 mg, 0.01 mmol, 0.01 equiv), and dichloromethane (5 mL). After the mixture was stirred for 30 min, (1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8- sulfonyl chloride (290 mg, 0.81 mmol, 1.00 equiv) was added. The resulting solution was stirred for 12 h at 20oC. The reaction mixture was diluted with 30 mL of dichloromethane and washed with water (10 mLx3). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/hexane (2:1). This resulted in 355 mg (75%) of tert-butyl 2- [(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8- sulfonyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate as a white solid. 1H-NMR (400 MHz,CDCl3): į 7.12(d, 1H), 6.32(s, 1H), 4.35-4.15(m, 3H), 3.60(s, 4H), 3.35(t, J = 12 Hz, 4H), 2.35-1.85(m, 9H), 1.74(t, J = 12 Hz, 4H), 1.45(s, 9H), 1.17-1.08(m, 2H), 1.03- 0.96(m, 2H) ppm. LCMS (method B, ESI): RT = 1.52 min, m/z = 450.2 [M-100]+.
Step 3: Synthesis of 5-cyclopropyl-N-[(1R,3r,5S)-8-[2,7-diazaspiro[3.5]nonane- 2-sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide trifluoroacetate
Figure imgf000323_0001
[0358] Into a 25-mL round-bottom flask was placed tert-butyl 2-[(1R,3r,5S)-3-(5- cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]-2,7- diazaspiro[3.5]nonane-7-carboxylate (50 mg, 0.09 mmol, 1.00 equiv), dichloromethane (10 mL) and trifluoroacetic acid (2.5 mL). The resulting solution was stirred for 4 h at room temperature. The reaction mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30%B to 70%B in 10 min; 254nm. This resulted in 36.5 mg (83%) of 5-cyclopropyl-N-[(1R,3r,5S)-8-[2,7-diazaspiro[3.5]nonane-2-sulfonyl]-8- azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide trifluoroacetate as a solid. 1H- NMR (300 MHz, D2O): į 6.28(s, 1H), 4.08(s, 3H), 3.66(s, 4H), 3.15-3.05(m, 4H), 2.24- 1.86(m, 13H), 1.08-099(m, 2H), 0.92-0.84(m, 2H) ppm. LCMS (method B, ESI): RT=1.67 min, m/z =450.0 [M+H]+. EXAMPLE 26
Synthesis of 5-ethyl-N-((1R,3r,5S)-8-(piperidin-4-ylmethylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide (Cpd. No. 562)
Figure imgf000324_0001
Step 1: Synthesis of ethyl 5-eth lisoxazole-3-carboxylate
Figure imgf000324_0002
[0359] Into a 250-mL round-bottom flask was placed ethyl 2,4-dioxohexanoate (10 g, 69.36 mmol, 1.00 equiv), ethanol (100 mL), and NH2OH-HCl (4.95 g, 70.23 mmol, 1.2 equiv). The resulting solution was stirred for 16 hours at 80oC in an oil bath. The reaction mixture was concentrated under vacuum and the residuedissolved in 50 mL of ethyl acetate. The resulting mixture was washed with 2x20 mL of water. The organic phase was dried and concentrated under vacuum. This resulted in 10 g (46%) of ethyl 5-ethyl- 1,2-oxazole-3-carboxylate as a yellow solid. LCMS (method A, ESI): RT = 1.37 min, m/z =170.0 [M+H]+.
Step 2: Synthesis of 5-ethyli x z l - - r xylic acid
Figure imgf000324_0003
[0360] Into a 250-mL round-bottom flask was placed ethyl 5-ethyl-1,2-oxazole-3- carboxylate (5g, 29.55 mmol, 1.00 equiv), ethanol (50 mL), and sodium hydroxide (2.4 g, 60.00 mmol, 2.03 equiv). This was followed by the addition of water (8 mL) dropwise with stirring over 10 mins. The resulting solution was stirred for 16 hours at 25oC. The pH value of the solution was adjusted to 4 with hydrochloric acid (6N). The resulting solution was extracted with 50 mL of dichloromethane. The resulting mixture was concentrated under vacuum. This resulted in 3 g (72%) of 5-ethyl-1,2-oxazole-3- carboxylic acid as a yellow solid.1H-NMR (300MHz, DMSO): į13.8(s, 1H), 6.58(s, 1H), 2.85(q, J1= 7.5 Hz, 2H), 1.32(t, J= 7.5 Hz, 3H) ppm. LCMS (method C, ESI): RT = 2.60 min, m/z = 142.0411.0 [M+H]+.
Step 3: Synthesis of (1R,3r,5S)-tert-butyl 3-(5-ethylisoxazole-3-carboxamido)-8- azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000325_0001
[0361] Into a 50-mL round-bottom flask was placed (1R,3r,5S)-tert-butyl 3-amino-8- azabicyclo[3.2.1]octane-8-carboxylate (300 mg, 1.33 mmol, 1.00 equiv), dichloromethane (13 mL), 5-ethyl-1,2-oxazole-3-carboxylic acid (480 mg, 3.40 mmol, 1.10 equiv), 1-hydroxybenzotrizole (431 mg, 3.19 mmol, 1.50 equiv), N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (1.2 g, 6.26 mmol, 3.00 equiv) and triethylamine (860 mg, 8.50 mmol, 4.00 equiv). The resulting solution was stirred for 16 h at 25oC. The reaction mixture was washed with 2x30 mL of H2O. The water layers were back extracted with 2x30 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (6:1). This resulted in 350 mg (76%) of (1R,3r,5S)-tert-butyl 3-(5-ethylisoxazole-3-carboxamido)-8-azabicyclo[3.2.1]octane- 8-carboxylateas a yellow solid. LCMS (method C, ESI): RT = 0.93 min, m/z = 350.0 [M+H]+.
Step 4: Synthesis of N-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5- ethylisoxazole-3-carboxamide
Figure imgf000325_0002
[0362] Into a 50-mL round-bottom flask was placed (1R,3r,5S)-tert-butyl 3-(5- ethylisoxazole-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (350 mg, 1.00 mmol, 1.00 equiv) anddichloromethane (30 mL). To the above hydrogen chloride (gas) was introduced. The resulting solution was stirred for 2 h at 25oC. The reaction mixture was concentrated under vacuum. This resulted in 300 mg (HCl salt) of N-[(1R,3r,5S)-8- azabicyclo[3.2.1]octan-3-yl]-5-ethyl-1,2-oxazole-3-carboxamide as a white solid. LCMS (method A, ESI): RT = 0.97 min, m/z = 250.0 [M+H]+.
Step 5: Synthesis of benzyl 4-(((1R,3r,5S)-3-(5-ethylisoxazole-3-carboxamido)- 8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate
Figure imgf000326_0001
[0363] Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed N-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-5-ethyl-1,2- oxazole-3-carboxamide (100 mg, 0.40 mmol, 1.00 equiv), and tetrahydrofuran (5 mL). This was followed by the addition of lithium bis(trimethylsilyl)amide (1N in THF, 1.5 mL) dropwise with stirring at -70oC. To this was added benzyl 4- [(chlorosulfonyl)methyl]piperidine-1-carboxylate (200 mg, 0.60 mmol, 1.50 equiv) in several portions at -70oC. The resulting solution was stirred for 30 min at -70oC in a dry ice bath. The reaction mixture was stirred for an additional 16 h at 25oC. The resulting solution was diluted with 30 mL of ethyl acetate andwashed with 2x15 mL of H2O. The resulting mixture was concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2:3). This resulted in 140 mg (64%) of benzyl 4-[[(1R,3r,5S)-3-(5-ethyl-1,2-oxazole-3-amido)-8- azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate as white solid. LCMS (method C, ESI): RT = 1.53 min, m/z = 545.0 [M+H]+.
Step 6: Synthesis of 5-ethyl-N-((1R,3r,5S)-8-(piperidin-4-ylmethylsulfonyl)-8- aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide
Figure imgf000326_0002
[0364] Into a 50-mL round-bottom flask was placed benzyl 4-[[(1R,3r,5S)-3-(5-ethyl- 1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1- carboxylate (120 mg, 0.22 mmol, 1.00 equiv) and hydrochloric acid (12N, 20 mL). The resulting solution was stirred for 2 h at 25oC. The reaction mixture was concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-025): Column, XBridge Prep Phenyl OBD Column,5um,19*150mm; mobile phase, Water with 10mmol NH4HCO3 and MeCN (20.0% MeCN up to 75.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 20.0% in 2 min); Detector, UV 254/220nm.This resulted in 34.8 mg (38%) of 5-ethyl- N-[(1 R,3r,5S)-8-[(piperidin-4-ylmethane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,2- oxazole-3-carboxamide as a white solid. 1H-NMR (400MHz, CD3OD): į 6.47(s, 1H), 4.26(d, J= 23.0 Hz, 2H), 4.16(d, J= 6.4 Hz, 1H), 3.14-3.06(m, 4H), 2.89(q, J1=7.6Hz, J2=15.2Hz, 2H), 2.76(q, J1=10.8Hz, J2= 12.8Hz, 2H), 2.32-2.26(m, 2H), 2.10-1.91(m, 9H), 1.44-1.38(m, 5H)ppm. LCMS (method C, ESI): RT = 2.60 min, m/z = 411.0 [M+H]+. EXAMPLE 27
Synthesis of N-((1R,3r,5S)-8-((1s,4S)-4-aminocyclohexylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride
(Cpd. No. 540)
Figure imgf000327_0001
[0365] Into a 5-L round-bottom flask was placed a solution of 5-cyclopropyl-N- ((1R,3r,5S)-8-((4-oxocyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide (3 g, 7.12 mmol, 1.00 equiv) in methanol (3 L). Then HCOONH4 (17.6 g, 279.12 mmol, 40.00 equiv) and acetic acid (852 mg, 14.19 mmol, 2.00 equiv) were added. After stirring for 30 min at 25oC, NaBH3CN (895 mg, 14.24 mmol, 2.00 equiv) was added. The resulting solution was stirred for 30 min at 25oC. The reaction mixture was concentrated under vacuum. The resulting solid was extracted with ethyl acetate (100 mL X 5). The combined organic layers were concentrated and the residue purified by flash chromatography (DCE:MeOH = 10:1). The product was further purified by Prep- HPLC with the following conditions: Column, X Bridge C18, 19*150 mm, 5 um ; mobile phase, Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN ; Flow rate: 20 mL/min; Detector, 254 nm. The fractions containing product were combined and concentrated, then acidified with hydrochloric acid (12N, 0.5mL), and concentrated again under vacuum. This resulted in 200 mg of N-((1R,3R,5S)-8-((1s,4S)-4- aminocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3- carboxamide hydrochloride as a light yellow solid. 1H-NMR (300 MHz, D2O): į 6.25(s, 1H), 4.15(s, 2H), 4.10-4.00(m, 1H), 3.42-3.25(m, 2H), 2.25-1.75(m, 17H), 1.09-1.00(m, 2H), 0.92-0.81(m, 2H) ppm. LCMS (method A, ESI): RT = 1.69 min, m/z = 445.2 [M+23]+. EXAMPLE 28
Synthesis of N-((1R,3r,5S)-8-(4-(2-aminopropan-2-yl)phenylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide (Cpd. No. 766)
Figure imgf000328_0001
Step 1: Synthesis of N-((1R,3r,5S)-8-(4-bromophenylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000328_0002
[0366] Into a 25-mL round-bottom flask was placed N-((1R,3r,5S)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (500 mg, 1.68 mmol, 1.00 equiv), and dichloromethane (10 mL). This was followed by the dropwise addition of TEA (510 mg, 5.04 mmol, 3.00 equiv) with stirring at 0oC. To this was added 4-bromobenzene-1-sulfonyl chloride (470 mg, 1.84 mmol, 1.10 equiv) in several batches at 0oC. The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 10 mL of dichloromethane. The resulting mixture was washed with 3x5 mL of H2O. The organic phase was collected and concentrated under vacuum. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 742 mg (92%) of N-((1R,3r,5S)-8-(4- bromophenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3- carboxamide as a white solid. 1H-NMR (300 MHz, CDCl3): į 7.78-7.70(m, 2H), 7.69- 7.60(m, 2H), 7.04(br, 1H), 6.30(s, 1H), 4.28(brs, 3H), 2.39-2.25(m, 2H), 2.11-2.00(m, 1H), 1.97-1.72(m, 6H), 1.18-1.07(m, 2H), 1.00-0.92(m, 2H) ppm. LCMS (Method D, ESI): RT=1.57 min, m/z =480.0 [M+H]+.
Step 2: Synthesis of 5-cyclopropyl-N-((1R,3r,5S)-8-(4-(prop-1-en-2- yl)phenylsulfonyl)-8-aza-bic clo 3.2.1 octan-3- l isoxazole-3-carboxamide
Figure imgf000329_0001
[0367] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed N-((1R,3r,5S)-8-(4-bromophenylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide (642 mg, 1.34 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (293 mg, 1.74 mmol, 1.30 equiv), Pd(dppf)Cl2 (98 mg, 0.13 mmol, 0.10 equiv), potassium carbonate (555 mg, 4.02 mmol, 3.00 equiv), 1,4-dioxane (15 mL) and water(1.5 mL). The resulting solution was stirred for 14 h at 90oC. The reaction mixture was concentrated under vacuum. The resulting solution was diluted with 25 mL of H2O and extracted with 3x10 mL of ethyl acetate.The organic layers were combined and dried over anhydrous sodium sulfate. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 544 mg (92%) of 5-cyclopropyl-N- ((1R,3r,5S)-8-(4-(prop-1-en-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide as a white solid. 1H-NMR (300 MHz, CDCl3): į 7.82(d, J =8.7 Hz, 2H), 7.56(d, J =8.7 Hz, 2H), 7.05(br, 1H), 6.30(s, 1H), 5.48(s, 1H), 5.24(s, 1H), 4.29(brs, 3H), 2.41-2.26(m, 2H), 2.17(s, 3H), 2.11-2.00(m, 1H), 1.97-1.70(m, 6H), 1.16- 1.05(m, 2H), 1.01-0.92(m, 2H) ppm. LCMS (Method D, ESI): RT = 1.59 min, m/z = 442.0 [M+H]+.
Step 3: Synthesis of N-((1R,3r,5S)-8-(4-(2-(2-chloroacetamido)propan-2- yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3- carboxamide
Figure imgf000330_0001
[0368] Into a 100-mL round-bottom flask was placed 5-cyclopropyl-N-((1 R,3r,5S)-8-(4- (prop-1-en-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide (544 mg, 1.23 mmol, 1.00 equiv), AcOH (39 mL), 2-chloroacetonitrile (1.85 g, 24.50 mmol, 19.89 equiv). This was followed by the dropwise addition of sulfuric acid (98%, 9.7 mL) with stirring at 0oC. The resulting solution was stirred for 14 h at 25oC. The reaction mixture was diluted with 100 mL of ice-water. The pH of the solution was adjusted to 7 with sodium carbonate (sat. aq.). The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. After concentration, the residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 505 mg (77%) of N- ((1R,3r,5S)-8-(4-(2-(2-chloroacetamido)propan-2-yl)phenylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide as a white solid. 1H- NMR (300 MHz, CDCl3): į 7.83(d, J =8.7 Hz, 2H), 7.48(d, J =8.4 Hz, 2H), 7.05(br, 1H), 6.85(brs, 1H), 6.30(s, 1H), 4.27(brs, 3H), 3.98(s, 2H), 2.40-2.26 (m, 2H), 2.11-2.00(m, 1H), 1.95-1.76(m, 6H), 1.75(s, 6H), 1.15-1.05(m, 2H), 1.00-0.91(m, 2H) ppm. LCMS (Method D, ESI): RT = 1.07 min, m/z = 535.0 [M+H]+.
Step 4: Synthesis of N-((1R,3r,5S)-8-(4-(2-aminopropan-2-yl)phenylsulfonyl)-8- aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide
Figure imgf000330_0002
[0369] Into a 25-mL round-bottom flask was placed N-((1R,3r,5S)-8-(4-(2-(2- chloroacetamido)propan-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide (593 mg, 1.11 mmol, 1.00 equiv), ethanol (6.0 mL), and thiourea (101 mg, 1.33 mmol, 1.20 equiv). This was followed by the dropwise addition of AcOH (1.2 mL) with stirring. The resulting solution was stirred for 12 h at 85oC. The reaction mixture was concentrated under vacuum. The residue was dissolved in 10 mL of ethyl acetate and washed with 2x5 mL of H2O. Concentraton yielded 465 mg (91%) of N-((1S,3r,5R)-8-(4-(2-aminopropan-2-yl)phenylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide as an off-white solid. The crude product (100 mg) was purified by Prep-HPLC with the following conditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/10mmol/L NH4HCO3, Mobile Phase B: MeOH; Flow rate: 30 mL/min; Gradient: 45%B to 75%B in 06 min; 254nm. 120 mL of fractions contained product was obtainedresulting in 18.4 mg of N-((1R,3r,5S)-8-(4-(2-aminopropan-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3- yl)-5-cyclopropylisoxazole-3-carboxamide as a white solid. 1H-NMR (400 MHz, CD3OD): į 7.87(d, J =8.8 Hz, 2H), 7.73(d, J =8.4 Hz, 2H), 6.35(s, 1H), 4.27(brs, 2H), 4.20-4.10(m, 1H), 2.32-2.21(m, 2H), 2.20-2.10(m, 1H), 2.00(d, J =14.4Hz, 2H), 1.93- 1.82(m, 2H), 1.63-1.55(m, 2H), 1.54(s, 6H), 1.18-1.10(m, 2H), 1.00-0.91(m, 2H) ppm. LCMS (Method A, ESI): RT=1.77 min, m/z = 481.0 [M+Na]+. EXAMPLE 29
Synthesis of 5-cyclopropyl-N-((1S,3r,5R)-8-((1-methylpiperidin-4-yl)methylsulfonyl)-8- aza-bicyclo[3.2.1 octan-3- l isoxazole-3-carboxamide (Cpd. No. 770)
Figure imgf000331_0001
Step 1: Synthesis of benzyl 4-((methylsulfonyloxy)methyl)piperidine-1- carboxylate
Figure imgf000331_0002
[0370] Into a 1000-mL round-bottom flask, was placed benzyl 4- (hydroxymethyl)piperidine-1-carboxylate (100 g, 401.11 mmol, 1.00 equiv), dichloromethane (300 mL), triethylamine (121 g, 1.20 mol, 3.00 equiv). This was followed by the addition of methanesulfonyl chloride (91.6 g, 799.64 mmol, 2.00 equiv) dropwise with stirring at 0oC. The resulting solution was stirred for 16 h at 25oC. The resulting mixture was washed with 2x500 mL of H2O. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 116 g (88%) of benzyl 4- ((methylsulfonyloxy)methyl)piperidine-1-carboxylate as a yellow solid. 1H-NMR (300 MHz, CDCl3): į 7.40-7.29(m, 5H), 5.07(s, 2H), 4.08-4.01(m, 4H), 3.17(s, 3H), 2.90- 2.70(m, 2H), 1.99-1.86(m, 1H), 1.69-1.66(m, 2H), 1.20-1.15(m, 2H)ppm. LCMS (method D, ESI): RT=1.46 min, m/z=328.0 [M+H]+.
Step 2: Synthesis of benzyl 4-(acetylthiomethyl)piperidine-1-carboxylate
Figure imgf000332_0001
[0371] Into a 2000-mL round-bottom flask, was placed benzyl 4- [(methanesulfonyloxy)methyl]piperidine-1-carboxylate (116 g, 354.31 mmol, 1.00 equiv), acetonitrile (1000 mL), 1-(potassiosulfanyl)ethan-1-one (190 g, 1.66 mol, 5.00 equiv). The resulting solution was stirred for 2 h at 80oC in an oil bath. The resulting solution was extracted with 2x500 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 105 g (96%) of benzyl 4-(acetylthiomethyl)piperidine-1-carboxylate as red oil. 1H- NMR (300 MHz, CDCl3): į 7.40-7.29(m, 5H), 5.12(s, 2H), 4.20-4.13(m, 2H), 2.83- 2.70(m, 4H), 2.34(s, 3H), 1.78-1.70(m, 2H), 1.68-1.57(m, 1H), 1.28-1.22(m, 2H) ppm. LCMS (method A, ESI): RT=1.53 min, m/z=308.0 [M+H]+
Step 3: Synthesis of benzyl 4-(chl r lf nylmethyl)piperidine-1-carboxylate
Figure imgf000332_0002
[0372] Into a 1000-mL round-bottom flask, was placed benzyl 4- [(acetylsulfanyl)methyl]piperidine-1-carboxylate (105 g, 341.57 mmol, 1.00 equiv), acetic acid (500 mL), water(250 mL). This was followed by the addition of N- chlorosuccinimide (160 g, 1.20 mol, 3.50 equiv) in several batches at 0oC. The resulting solution was stirred for 2 h at 25oC. The resulting solution was extracted with 2x500 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 95 g (84%) of benzyl 4-(chlorosulfonylmethyl)piperidine-1-carboxylate as a light yellow solid. 1H-NMR (300 MHz, CDCl3): į 7.41-7.28(m, 5H), 5.12(s, 2H), 4.24-4.08 (m, 2H), 3.65(d, J=6.3 Hz, 2H), 2.89-2.73(m, 3H), 2.43-2.31(m, 1H), 2.07- 1.95(m, 2H), 1.43-1.21(m, 2H) ppm. LCMS (method A, ESI): RT=1.48 min, m/z=332.0 [M+H]+.
Step 4: Synthesis of benzyl 4-(((1S,3r,5R)-3-(5-cyclopropylisoxazole-3- carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate bz
Figure imgf000333_0001
[0373] Into a 1000-mL round-bottom flask, was placed N-((1S,3r,5R)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride (28.4 g, 95.37 mmol, 1.00 equiv), dichloromethane (500 mL), triethylamine (100 g, 988.24 mmol, 10.00 equiv). This was followed by the addition of benzyl 4- [(chlorosulfonyl)methyl]piperidine-1-carboxylate (35 g, 105.48 mmol, 1.10 equiv) in several batches at -70oC. The resulting solution was stirred for 16 h at 25oC. The resulting mixture was washed with 2x300 mL of H2O. The organic phase was collected. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 34 g (64%) of benzyl 4-(((1S,3r,5R)-3-(5-cyclopropylisoxazole-3-carboxamido)-8-aza- bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate as a white solid. 1H- NMR (300 MHz, CDCl3): į 7.36-7.26(m, 5H), 7.10(d, J=7.2 Hz, 1H), 6.32(s, 1H), 5.12(s, 2H), 4.31-4.16(m, 5H), 2.92-2.84(m, 4H), 2.31-1.92(m, 12H), 1.31 -1.24(m, 2H), 1.14-1.09(m, 2H), 1.01-0.97(m, 2H) ppm. LCMS (method B, ESI): RT=1.59 min, m/z=557.0[M+H]+. Step 5: Synthesis of 5-cyclopropyl-N-((1S,3r,5R)-8-(piperidin-4- ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide
hydrochloride
Figure imgf000334_0001
[0374] Into a 1000-mL round-bottom flask, was placed benzyl 4-(((1S,3r,5R)-3-(5- cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8- ylsulfonyl)methyl)piperidine-1-carboxylate (48 g, 86.23 mmol, 1.00 equiv), hydrochloric acid (12 N, 500 mL). The resulting solution was stirred for 8 h at 25oC. The resulting mixture was concentrated under vacuum. This resulted in 39 g (99%) of 5-cyclopropyl- N-((1S,3r,5R)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide hydrochloride as an off-white solid. LCMS (method A, ESI): RT= 0.99 min, m/z=423.0[M+H]+
Step 6: Synthesis of 5-cyclopropyl-N-((1S,3r,5R)-8-((1-methylpiperidin-4- yl)methylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide
Figure imgf000334_0002
[0375] In Into a 2000-mL round-bottom flask, was placed 5-cyclopropyl-N-((1S,3r,5R)- 8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide hydrochloride (42 g, 91.50 mmol, 1.00 equiv), methanol (800 mL), formaldehyde (40 mL), acetic acid (8 mL). The resulting solution was stirred for 0.5 h at 25oC. This was followed by the addition of sodium cyanoborohydride (11 g, 175.05 mmol, 2.00 equiv) in several batches at 0oC. The resulting solution was stirred for 2 h at 25oC. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 10 with sodium hydroxide (1 N). The resulting solution was extracted with 2x500 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. This resulted in 38.9 g (98%) of 5-cyclopropyl-N-((1S,3r,5R)-8-((1-methylpiperidin-4- yl)methylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide as an off- white solid. 1H-NMR (300 MHz, CD3OD): į 6.41(s, 1H), 4.28-4.18 (m, 3H), 3.10(d, J=6.0 Hz, 2H), 2.94(d, J=12.0 Hz, 2H), 2.34-1.95(m, 17H), 1.60-1.40(m, 2H), 1.21- 1.15(m, 2H), 1.05-0.98(m, 2H) ppm. LCMS (method B, ESI): RT=1.64 min, m/z=437.1[M+H]+. EXAMPLE 30
SMYD3 Biochemical Assay
General Materials
[0376] S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), Tris, Tween20, dimethylsulfoxide (DMSO), bovine skin gelatin (BSG), and Tris(2- carboxyethyl)phosphine hydrochloride solution (TCEP) were purchased from Sigma- Aldrich at the highest level of purity possible. 3H-SAM was purchase from American Radiolabeled Chemicals with a specific activity of 80 Ci/mmol. 384-well opaque white OptiPlates and SPA beads (Perkin Elmer, catalog # RPNQ0013) were purchased from PerkinElmer.
Substrates
[0377] N-terminally GST-tagged MEKK2 (MAP3K2) protein corresponding to reference sequence AAF63496.3 was purchased from Life Technologies (catalog # PV4010). This protein was expressed in High Five insect cells and purified to >85 % purity. Protein identity was confirmed by MS/MS analysis after proteolytic digestion. The protein sequence used was:
MAPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNK KFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERA EISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDR LCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCF KKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLVPRH NQTSLYKKAGTMDDQQALNSIMQDLAVLHKASRPALSLQETRKA KSSSPKKQNDVRVKFEHRGEKRILQFPRPVKLEDLRSKAKIAFGQS MDLHYTNNELVIPLTTQDDLDKALELLDRSIHMKSLKILLVINGST QATNLEPLPSLEDLDNTVFGAERKKRLSIIGPTSRDRSSPPPGYIPDE LHQVARNGSFTSINSEGEFIPESMEQMLDPLSLSSPENSGSGSCPSL DSPLDGESYPKSRMPRAQSYPDNHQEFSDYDNPIFEKFGKGGTYPR RYHVSYHHQEYNDGRKTFPRARRTQGNQLTSPVSFSPTDHSLSTSS
Figure imgf000336_0001
Molecular Biology
[0378] Full-length human SMYD3 isoform 1 (BAB86333) was inserted into a modified pET21b plasmid containing a His6 tag and TEV and SUMO cleavage sites. Because two common variants of SMYD3 exist in the population, site directed mutagenesis was subsequently performed to change amino acid 13 from an asparagine to a lysine, resulting in plasmid pEPZ533. A lysine at position 13 conforms to the more commonly occurring sequence (NP 001 161212).
Protein Expression
[0379] E. coli (BL21 codonplus RIL strain, Stratagene) were transformed with plasmid pEPZ553 by mixing competent cells and plasmid DNA and incubating on ice for 30 minutes followed by heat shock at 42 °C for 1 minute and cooling on ice for 2 minutes. Transformed cells were grown and selected on LB agar with 100 μg/mL ampicillin and 17 μg/mL chloramphenicol at 37 °C overnight. A single clone was used to inoculate 200 mL of LB medium with 100 μg/mL ampicillin and 17 μg/mL chloramphenicol and incubated at 37 °C on an orbital shaker at 180 rpm. Once in log growth, the culture was diluted 1 : 100 into 2 L of LB medium and grown until OD60o was about 0.3 after which the culture was incubated at 15 °C and 160 rpm. Once OD6oo reached about 0.4, IPTG was added to a final concentration of 0.1 mM and the cells were grown overnight at 15 °C and 160 rpm. Cells were harvested by centrifugation at 8000 rpm, for 4 minutes at 4 °C and stored at -80 °C for purification.
Protein Purification
[0380] Expressed full-length human His-tagged SMYD3 protein was purified from cell paste by Nickel affinity chromatography after equilibration of the resin with Buffer A (25 mM Tris, 200 mM NaCl, 5% glycerol, 5 mM β-mercaptoethanol, pH7.8). The column was washed with Buffer B (Buffer A plus 20 mM imidazole) and His-tagged SMYD3 was eluted with Buffer C (Buffer A plus 300 mM imidazole). The His tag, TEV and SUMO cleavage sites were removed generating native SMYD3 by addition of ULP1 protein at a ratio of 1:200 (ULP1:SMYD3). Imidazole was removed by dialysis overnight in Buffer A. The dialyzed solution was applied to a second Nickel column and the native SMYD3 protein was collected from the column flow-through. The flow- through was dialyzed in Buffer D (25 mM Tris, 5% glycerol, 5 mM E-mercaptoethanol, 50 mM NaCl, pH7.8) and ULP1 was removed using a Q sepharose fast flow column. SMYD3 was eluted in Buffer A and further purified using an S200 size-exclusion column equilibrated with Buffer A. SMYD3 was concentrated to 2 mg/mL with a final purity of 89%.
Predicted Translation:
[0381] SMYD3 (Q9H7B4)
MEPLKVEKFATAKRGNGLRAVTPLRPGELLFRSDPLAYTVCKGSR GVVCDRCLLGKEKLMRCSQCRVAKYCSAKCQKKAWPDHKRECK CLKSCKPRYPPDSVRLLGRVVFKLMDGAPSESEKLYSFYDLESNIN KLTEDKKEGLRQLVMTFQHFMREEIQDASQLPPAFDLFEAFAKVIC NSFTICNAEMQEVGVGLYPSISLLNHSCDPNCSIVFNGPHLLLRAV RDIEVGEELTICYLDMLMTSEERRKQLRDQYCFECDCFRCQTQDK DADMLTGDEQVWKEVQESLKKIEELKAHWKWEQVLAMCQAIISS NSERLPDINIYQLKVLDCAMDACINLGLLEEALFYGTRTMEPYRIFF PGSHPVRGVQVMKVGKLQLHQGMFPQAMKNLRLAFDIMRVTHG REHSLIEDLILLLEECDANIRAS. (SEQ ID No. 2).
General Procedure for SMYD3 Enzyme Assays on MEKK2 protein substrate
[0382] The assays were all performed in a buffer consisting of 25 mM Tris-Cl pH 8.0, 1 mM TCEP, 0.005% BSG, and 0.005% Tween 20, prepared on the day of use. Compounds in 100% DMSO (1ul) were spotted into a 384-well white opaque OptiPlate using a Bravo automated liquid handling platform outfitted with a 384-channel head (Agilent Technologies). DMSO (1ul) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 1ul of SAH, a known product and inhibitor of SMYD3, was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control. A cocktail (40ul) containing the SMYD3 enzyme was added by Multidrop Combi (Thermo-Fisher). The compounds were allowed to incubate with SMYD3 for 30 min at room temperature, then a cocktail (10ul) containing SAM and MEKK2 was added to initiate the reaction (final volume = 51ul). The final concentrations of the components were as follows: SMYD3 was 0.4 nM, 3H-SAM was 8 nM, MEKK2 was 12 nM, SAH in the minimum signal control wells was 1 mM, and the DMSO concentration was 2%. The assays were stopped by the addition of non-radiolabeled SAM (10ul) to a final concentration of 100 uM, which dilutes the 3H-SAM to a level where its incorporation into MEKK2 is no longer detectable. Radiolabeled MEKK2 was detected using a scintillation proximity assay (SPA). 10 uL of a 10 mg/mL solution of SPA beads in 0.5 M citric acid was added and the plates centrifuged at 600 rpm for 1 min to precipitate the radiolabeled MEKK2 onto the SPA beads. The plates were then read in a PerkinElmer TopCount plate reader to measure the quantity of 3H-labeled MEKK2 as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).
% inhibition calculation
Figure imgf000338_0002
[0383] Where dpm = disintegrations per minute, cmpd = signal in assay well, and min and max are the respective minimum and maximum signal controls.
Four-parameter IC50 fit
Figure imgf000338_0001
[0384] Where top and bottom are the normally allowed to float, but may be fixed at 100 or 0 respectively in a 3-parameter fit. The Hill Coefficient normally allowed to float but may also be fixed at 1 in a 3-parameter fit. Y is the % inhibition and X is the compound concentration.
[0385] SMYD3 biochemical assay data for representative Compounds of the Disclosure are presented in Tables 1A, 2A, and 3A in the column titled "SMYD3Biochem IC50 (μM)." EXAMPLE 31
SMYD3 Cell Assay Trimethyl-MEKK2-In-Cell Western Assay
[0386] 293T/17 adherent cells were purchased from ATCC (American Type Culture Collection), Manassas, VA, USA. MEM/Glutamax medium, Optimem Reduced Serum medium, penicillin-streptomycin, 0.05% trypsin and 1x D-PBS were purchased from Life Technologies, Grand Island, NY, USA. PBS-10X was purchased from Ambion, Life Technologies, Grand Island, New York, USA. PBS with Tween 20 (PBST (10x)) was purchased from KPL, Gaithersburg, Maryland,USA. Tet System FBS- approved FBS US Source was purchased from Clontech, Mountain View, California, USA. Odyssey blocking buffer, 800CW goat anti-rabbit IgG (H+L) antibody, 680CW Goat anti-mouse IgG (H+L) and Licor Odyssey infrared scanner were purchased from Licor Biosciences, Lincoln, NE, USA. Tri-methyl-Lysine [A260]-MEKK2 antibody, MEKK2 and SMYD3 plasmids were made at Epizyme. Anti-flag monoclonal mouse antibody was purchased from Sigma, St. Louis, MO, USA. Methanol was purchased from VWR, Franklin, MA, USA. 10% Tween 20 was purchased from KPL, Inc., Gaithersburg, Maryland, USA. Fugene was purchased from Promega, Madison, WI, USA. The Biotek ELx405 was purchased from BioTek, Winooski, Vermont, USA. The multidrop combi was purchased from Thermo Scientific, Waltham, Massachusetts, USA.
[0387] 293T/17 adherent cells were maintained in growth medium (MEM/Glutamax medium supplemented with 10% v/v Tet System FBS and cultured at 37 °C under 5% CO2.
Cell treatment, In Cell Western (ICW) for detection of trimethyl-lysine-MEKK2 and MEKK2.
[0388] 293T/17 cells were seeded in assay medium at a concentration of 33,333 cells per cm2 in 30 mL medium per T150 flask and incubated at 37 °C under 5% CO2. Plasmids were prepared for delivery to cells by first mixing 1350 μL Opti-MEM with Fugene (81 μL) in a sterile Eppendorf and incubated for five minutes at room temperature (RT). MEKK2-flag (13.6 ug/T150) MEKK2 p3XFlag-CMV-14 with C-3XFlag and SMYD3 (0.151 ug/T150) SMYD3 p3XFlag-CMV-14 without C-3XFlag plasmids were aliquotted to a 1.7 mL sterile microfuge tube. The gene ID for MEKK2 and SMYD3 is NM_006609.3 and Q9H7B4, respectively. Entire volume of Opti-MEM/Fugene mixture was then added to a microfuge tube containing DNA plasmid, mixed and then incubated x 15 minutes at RT. The medium on the 293T/17 cells was refreshed, and the DNA/Fugene complex is added aseptically to each flask, rocked gently, and incubated at 37 C for 5 hours. Medium was then removed, and cells were washed once with PBS in the flask. Trypsin 0.05% (3mL) was added and cells incubated for three minutes. Room temperature MEM+10% Tet system FBS was added and cells were mixed gently, and counted using the Vi-cell. Cells were seeded at 100,000 cells/mL in 50 μL MEM/10%Tet FBS/Pen/Strep to a 384 well black/clear poly-D-lysine coated plate containing test agent diluted in DMSO. The final top concentration of test compound was 40 μM. The total concentration of DMSO did not exceed 0.2% (v/v). Plates were incubated x 30 minutes at RT in low-airflow area, followed by incubation at 37 °C under 5% CO2 for 24 hours. Medium was aspirated from all wells of assay plates prior to fixation and permeabilization with ice cold (-20 ºC) methanol (90 μL/well) for ten minutes. Plates were rinsed with PBS three times on BioTek ELx405. PBS was removed with a final aspiration, and Odyssey blocking buffer (50 μL/well) was added to each well and incubated for one hour at RT. Primary antibody solution was prepared (anti-trimethyl-MEKK2 at 1:600 dilution plus mouse anti-flag antibody at 1:10,000 dilution in diluent (Odyssey Blocking buffer + 0.1% Tween 20)) and 20 μL per well was dispensed using the Multidrop Combi. Assay plates were then sealed with foil, and incubated overnight at 4º C. Plates were washed five times with PBS-Tween (1X) on Biotek ELx405 and blotted on paper towel to remove excess reagent. Detection antibody solution (IRDye 800 CW goat anti-rabbit IgG diluted 1:400 in diluent (Odyssey Blocking buffer + 0.1% Tween 20), plus IRDye 680CW goat anti-mouse IgG at 1:500 in diluent (Odyssey Blocking buffer + 0.1% Tween 20) was added (20 μL/well) and incubated in dark for one hour at RT. Plates were then washed four times with PBS-T (1X) on ELx405. A final rinse with water was performed (115 μL/well x three washes on the ELx405). Plates were then centrifuged upside down, on paper towel, at 200 x g to remove excess reagent. Plates were left to dry in dark for one hour. The Odyssey Imager was used to measure the integrated intensity of 700 and 800 wavelengths at resolution of 84 μm, medium quality, focus offset 4.0, 700 channel intensity = 3.5 to measure the MEKK2-flag signal, 800 channel intensity = 5 to measure the Trimethyl-MEKK2 signal of each well.
Calculations:
[0389] First, the ratio for each well was determined b :
Figure imgf000340_0001
[0390] Each plate included fourteen control wells of DMSO only treatment (Minimum Inhibition) as well as fourteen control wells for maximum inhibition (Background). The average of the ratio values for each control type was calculated and used to determine the percent inhibition for each test well in the plate. Reference compound was serially diluted two-fold in DMSO for a total of nine test concentrations, beginning at 40 μM. Percent inhibition was calculated (below).
Figure imgf000341_0001
[0391] Non-linear regression curves were generated to calculate the IC50 and dose-response relationship using triplicate wells per concentration of compound.
[0392] SMYD3 cell assay data for representative Compounds of the Disclosure are presented in Tables 1A, 2A, and 3A in the column titled "SMYD3 Cell IC50 (μM)." EXAMPLE 32
SMYD2 ASSAY General Materials
[0393] S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), bicine, Tween20, dimethylsulfoxide (DMSO), bovine skin gelatin (BSG), and Tris(2- carboxyethyl)phosphine hydrochloride (TCEP) were purchased from Sigma-Aldrich at the highest level of purity possible. 3H-SAM was purchase from American Radiolabeled Chemicals with a specific activity of 80 Ci/mmol. 384-well streptavidin Flashplates were purchased from PerkinElmer.
Substrates
[0394] Peptide was synthesized with a N-terminal linker-affinity tag motif and a C-terminal amide cap by 21st Century Biochemicals. The peptide was high high-perfomance liquid chromatography (HPLC) purified to greater than 95% purity and confirmed by liquid chromatography mass spectrometry (LC-MS). The sequence was ARTKQTARKSTGGKAPRKQLATKAARKSA(K-Biot)-amide. (SEQ ID NO:3) Production of Recombinant SMYD2 Enzymes for Biochemical Enzyme Activity Assays
[0395] Full length SMYD2 (NP_064582.2) was cloned into a pFastbac-Htb-lic vector with an N-terminal His6 tag and FLAG tag, preceded by a TEV protease cleavage site. The protein was expressed in Sf9 insect cells. Cells were resuspended in lysis buffer (25 mM HEPES-NaOH, pH 7.5, 200 mM NaCl, 5% glycerol, and 5 mM ȕ-ME) and lysed by sonication. The protein was purified by Ni-NTA (Qiagen), followed by TEV cleavage to remove the His6 tag, subtractive Ni-NTA (Qiagen), and gel filtration chromatography using an S200 column (GE Healthcare). Purified protein was stored in 20 mM Tris-HCl, pH 8.0, 100 mM NaCl, and 1 mM TCEP.
General Procedure for SMYD2 Enzyme Assays on Peptide Substrates
[0396] The assays were all performed in a buffer consisting of 20mM Bicine (pH=7.6), 1mM TCEP, 0.005% Bovine Skin Gelatin, and 0.002% Tween20, prepared on the day of use. Compounds in 100% DMSO (1ul) were spotted into a polypropylene 384-well V- bottom plates (Greiner) using a Platemate Plus outfitted with a 384-channel head (Thermo Scientific). DMSO (1ul) was added to Columns 11, 12, 23, 24, rows A-H for the maximum signal control and 1ul of SAH, a known product and inhibitor of SMYD2, was added to columns 11, 12, 23, 24, rows I-P for the minimum signal control. A cocktail (40ul) containing the SMYD2 enzyme was added by Multidrop Combi (Thermo-Fisher). The compounds were allowed to incubate with SMYD2 for 30 min at room temperature, then a cocktail (10ul) containing 3H-SAM and peptide was added to initiate the reaction (final volume = 51ul). The final concentrations of the components were as follows: SMYD2 was 1.5nM, 3H-SAM was 10nM, and peptide was 60nM, SAH in the minimum signal control wells was 1000uM, and the DMSO concentration was 2%. The assays were stopped by the addition of non-radioactive SAM (10ul) to a final concentration of 600uM, which dilutes the 3H-SAM to a level where its incorporation into the peptide substrate is no longer detectable. 50ul of the reaction in the 384-well polypropylene plate was then transferred to a 384-well Flashplate and the biotinylated peptides were allowed to bind to the streptavidin surface for at least 1 hour before being washed three times with 0.1%Tween20 in a Biotek ELx405 plate washer. The plates were then read in a PerkinElmer TopCount plate reader to measure the quantity of 3H-labeled peptide bound to the Flashplate surface, measured as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).
% inhibition calculation
Figure imgf000342_0001
[0397] Where dpm = disintegrations per minute, cmpd = signal in assay well, and min and max are the respective minimum and maximum signal controls.
Four-parameter IC50 fit
Figure imgf000342_0002
[0398] Where top and bottom are the normally allowed to float, but may be fixed at 100 or 0 respectively in a 3-parameter fit. The Hill Coefficient normally allowed to float but may also be fixed at 1 in a 3-parameter fit. I is the compound concentration.
[0399] Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof.
[0400] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
[0401] All patents and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

What is Claimed Is: 1. A compound having Formula I:
Figure imgf000344_0001
or a pharmaceutically acceptable salt or hydrate thereof, wherein: B is:
Figure imgf000344_0002
;
X is selected from the group consisting of -S(=O)2-, S(=O)2N(R7)-, -S(=O)2C(R8)(H)-, -C(=O)-, -C(=O)N(R7)-, -C(=O)O-, -C(=O)C(R8)(H)-, and -S(=O)2N(R7)C(=O)N(R11)-; or X is absent; wherein the sulfur atom of -S(=O)2N(R7)-, -S(=O)2C(R8)(H)-, or -S(=O)2N(R7)C(=O)N(R11)- is attached to the nitrogen atom of B, the carbon atom of -C(=O)N(R7)- or -C(=O)O- is attached to the nitrogen atom of B, and the carbonyl carbon atom of -C(=O)C(R8)(H)- is attached the nitrogen atom of B; Z is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, [(cycloalkyl)alkylamino]alkyl, [(heterocyclo)alkylamino]alkyl, alkoxyalkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C3-12 cycloalkyl, aralkyl, and heteroaralkyl; R1 is selected from the group consisting of ethyl, n-propyl, isopropyl, isobutyl, and cyclopropyl; R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl; or R2a and R2b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R3a, R3b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or R3a and R3b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or R4a and R4b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R3a, R3b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or R5a and R5b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R3a, R3b, R4a, and R4b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or R2a and R5a taken together form a C1-4 bridge; and R2b, R3a, R3b, R4a, R4b, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or R3a and R4a taken together form a C1-4 bridge; and R2a, R2b, R3b, R4a, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or R2a and R4a taken together form a C1-4 bridge; and R2b, R3a, R3b, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or R3a and R5a taken form a C1-4 bridge; and R2a, R2b, R3b, R4a, R4b, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; R6 is selected from the group consisting of hydrogen and C1-4 alkyl; R7 is selected from the group consisting of hydrogen and C1-4 alkyl; R8 is selected from the group consisting of hydrogen, C1-4 alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and -N(R9)C(=O)R10; R9 is selected from the group consisting of hydrogen and C1-4 alkyl; R10 is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, and R11 is selected from the group consisting of hydrogen and C1-4 alkyl. with the proviso that said compound having Formula I is not: 5-cyclopropyl-N-(piperidin-4-yl)isoxazole-3-carboxamide; N-(8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide; N-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide; 5-cyclopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide; N-(1-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide; 5-cyclopropyl-N-(1-isobutyrylpiperidin-4-yl)isoxazole-3-carboxamide; N-(1-benzoylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide; ethyl 4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate; 5-cyclopropyl-N-(1-(furan-3-carbonyl)piperidin-4-yl)isoxazole-3-carboxamide; 5-cyclopropyl-N-(1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide; 5-cyclopropyl-N-(1-tosylpiperidin-4-yl)isoxazole-3-carboxamide; 5-cyclopropyl-N-(1-(2,6-dimethylpyrimidin-4-yl)piperidin-4-yl)isoxazole-3- carboxamide; N-(1-((4-acetamidophenyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide; 5-cyclopropyl-N-(1-(4-isopropyl-5-(pyridin-4-yl)pyrimidin-2-yl)piperidin-4- yl)isoxazole-3-carboxamide; N-(1-(7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)piperidin-4-yl)-5- ethylisoxazole-3-carboxamide; or 5-ethyl-N-(1-(4-isopropyl-5-(pyridin-4-yl)pyrimidin-2-yl)piperidin-4- yl)isoxazole-3-carboxamide.
2. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000347_0001
.
3. The compound of claim 2, or a pharmaceutically acceptable salt or hydrate thereof, wherein R6 is selected from the group consisting of hydrogen and methyl.
4. The compound of claim 3, or a pharmaceutically acceptable salt or hydrate thereof, wherein R6 is hydrogen.
5. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000348_0001
;
and R2a is selected from the group consisting of halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl.
6. The compound of claim 5 or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:
Figure imgf000348_0002
.
7. The compound of claims 5 or 6, or a pharmaceutically acceptable salt or hydrate thereof, wherein R2a is selected from the group consisting of methyl, ethyl, phenyl, -CH2Ph, -CF3, -CO2Et, and -CH2OH.
8. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000348_0003
;
and R3a is selected from the group consisting of halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl.
9. The compound of claim 8, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:
Figure imgf000348_0004
.
10. The compound of claims 8 or 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3a is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, and -CH2Ph.
11. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000349_0001
and R2a and R2b are each independently selected from the group consisting of halo and C1-6 alkyl; or R2a and R2b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl.
12. The compound of claim 11, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:
Figure imgf000349_0002
R2a and R2b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl.
13. The compound of claims 11 or 12, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of: ,
,
Figure imgf000349_0003
.
Figure imgf000350_0001
14. The compound of claim 11, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the rou consistin of:
Figure imgf000350_0002
,
and R2a and R2b are each independently selected from the group consisting of halo and C1-4 alkyl.
15. The compound of claims 11 or 14, or a pharmaceutically acceptable salt or hydrate thereof, wherein R2a and R2b are selected from the group consisting of fluoro and methyl.
16. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000350_0003
;
R3a and R3b are each independently selected from the group consisting of halo and C1-6 alkyl; or R3a and R3b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl.
17. The compound of claim 16, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the rou consistin of:
Figure imgf000350_0004
and R3a and R3b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl.
18. The compound of claims 16 or 17, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of: ,
.
.
Figure imgf000351_0001
19. The compound of claim 16, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the rou consistin of:
Figure imgf000351_0002
and R3a and R3b are each independently selected from the group consisting of halo and C1-4 alkyl.
20. The compound of claims 16 or 19, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3a and R3b are selected from the group consisting of fluoro and methyl.
21. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is :
Figure imgf000351_0003
R3a and R5a are each independently C1-6 alkyl; or R3a and R5a taken together form a C1-4 bridge.
22. The compound of claim 21, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the rou consistin of:
Figure imgf000352_0001
23. The compound of claim 22, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3a and R5a are each independently C1-4 alkyl.
24 The compound of claim 23, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3a and R5a are each methyl or ethyl.
25. The compound of claim 21, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000352_0002
.
26. The compound of claim 25, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the rou consistin of:
Figure imgf000352_0003
.
27. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000353_0001
wherein R2a and R3a are each independently C1-6 alkyl.
28. The compound of claim 27, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000353_0002
29. The compound of claim 28, or a pharmaceutically acceptable salt or hydrate thereof, wherein R2a and R3a are each independently C1-4 alkyl.
30. The compound of claim 29, or a pharmaceutically acceptable salt or hydrate thereof, wherein R2a and R3a are each methyl or ethyl.
31. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000353_0003
wherein R3a and R4a are each independently C1-6 alkyl; or R3a and R4a taken together form a C1-4 bridge.
32. The compound of claim 31, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is: ,
.
Figure imgf000354_0001
33. The compound of claim 32 or a pharmaceutically acceptable salt or hydrate thereof, wherein R3a and R4a are each independently C1-4 alkyl.
34. The compound of claim 33, or a pharmaceutically acceptable salt or hydrate thereof, wherein R3a and R4a are each methyl or ethyl.
35. The compound of claim 34, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the rou consistin of:
Figure imgf000354_0002
.
36. The compound of claim 35, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the rou consistin of:
Figure imgf000354_0003
.
37. The compound of claim 35, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:
Figure imgf000354_0004
.
38. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000355_0001
wherein R2a and R5a are each independently selected from the group consisting of C1-6 alkyl and alkoxycarbonyl; or R2a and R5a taken together form a C1-4 bridge. 39. The compound of claim 38, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:
Figure imgf000355_0002
40. The compound of claim 39, or a pharmaceutically acceptable salt or hydrate thereof, wherein R2a and R5a are each independently selected from the group consisting of C1-4 alkyl and alkoxycarbonyl.
41. The compound of claim 40, or a pharmaceutically acceptable salt or hydrate thereof, wherein R2a and R5a are each independently selected from the group consisting of methyl and -CO2Me.
42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is -S(=O)2-.
43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is -C(=O)-.
44. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is absent.
45. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is -S(=O)2N(H)-.
46. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is -C(=O)N(H)-.
47. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is -C(=O)O-.
48. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is -S(=O)2CH2-.
49. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is -C(=O)CH2-.
50 The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is selected from the group consisting of:
Figure imgf000356_0002
and and
Figure imgf000356_0001
R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and -N(R9)C(=O)R10.
51. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is selected from the group consisting of:
Figure imgf000357_0001
; and
R8 is selected from the group consisting of C1-4 alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and -N(R9)C(=O)R10.
52. The compound of claims 50 or 51, or a pharmaceutically acceptable salt or hydrate thereof, wherein R8 is selected from the group consisting of -NH2, -CH2NH2, and -N(H)C(=O)R10.
53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (aralkylamino)alkyl, optionally substituted C6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and optionally substituted C3-12 cycloalkyl.
54. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein one or more of R2a, R3a, R4a, and R5a is independently selected from the group consisting of halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl.
55. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein R6 is C1-4 alkyl.
56. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein: R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, C1-6 alkyl, C3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C6-14 aryl, aralkyl, and alkoxycarbonyl; or R2a and R2b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R3a, R3b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or R3a and R3b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R4a, R4b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or R4a and R4b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R3a, R3b, R5a, and R5b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl; or R5a and R5b taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and R2a, R2b, R3a, R3b, R4a, and R4b are each independently selected from the group consisting of hydrogen, halo, and C1-4 alkyl.
57. The compound of claim 1 having Formula III:
Figure imgf000358_0001
or a pharmaceutically acceptable salt or hydrate thereof.
58. The compound of claim 1 having Formula IV:
Figure imgf000358_0002
or a pharmaceutically acceptable salt or hydrate thereof.
59. The compound of claim 1 having Formula V:
Figure imgf000359_0001
or a pharmaceutically acceptable salt or hydrate thereof.
60. The compound of claim 1 having Formula VI:
Figure imgf000359_0002
or a pharmaceutically acceptable salt or hydrate thereof.
61. The compound of claim 1 having Formula VII:
Figure imgf000359_0003
or a pharmaceutically acceptable salt or hydrate thereof.
62. The compound of claim 1 having Formula VIII:
Figure imgf000359_0004
or a pharmaceutically acceptable salt or hydrate thereof.
63. The compound of claim 1 having Formula IX:
Figure imgf000359_0005
or a pharmaceutically acceptable salt or hydrate thereof.
64. The compound of claim 1 having Formula X:
Figure imgf000360_0001
or a pharmaceutically acceptable salt or hydrate thereof.
65. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is ethyl.
66. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is cyclopropyl.
67. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C6-14 aryl, and optionally substituted 4- to 14-membered heterocyclo.
68. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is (heterocyclo)alkyl.
70. The compound of claim 69, or a pharmaceutically acceptable salt or hydrate thereof, wherein said (heterocyclo)alkyl is:
Figure imgf000361_0001
R12 is selected from the group consisting of hydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl.
71. The compound of claim 70, or a pharmaceutically acceptable salt or hydrate thereof, wherein R12 is selected from the group consisting of hydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl
72. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is selected from the rou consistin of:
Figure imgf000361_0002
.
73. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, selected from any one or more of the compounds provided in Table 1, Table 1A, Table 2, Table 2A, Table 3, or Table 3A of the specification.
74. A pharmaceutical composition comprising the compound of any one of claims 1-73, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
75. A method of treating a patient comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-73, or a pharmaceutically acceptable salt or hydrate thereof, wherein the patient has cancer.
76. The method of claim 75, wherein the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B- cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
77. The pharmaceutical composition of claim 74 for use in treating cancer.
78. The pharmaceutical composition of claim 77, wherein the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
79. A compound of any one of claims 1-73, or a pharmaceutically acceptable salt or hydrate thereof, for use in treatment of cancer.
80. The compound of claim 79, wherein the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B- cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
81. Use of a compound of any one of claims 1-73, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture of a medicament for treatment of cancer.
82. The use of claim 81, wherein the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B- cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
83. A kit comprising the compound of any one of claims 1-73, or a pharmaceutically acceptable salt or hydrate thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt or hydrate thereof, to a patient having cancer.
84. The kit of claim 83, wherein the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B- cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
85. A method of treating a SMYD protein mediated disorder comprising administering to a subject in need thereof a compound of any one of claims 1-73, or a pharmaceutically acceptable salt or hydrate thereof in an effective amount to treat the SMYD protein mediated disorder.
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